UA119147C2 - Sulfonamides as modulators of sodium channels - Google Patents

Abstract

The invention relates to compounds of formula I or pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels: (I). The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders, including pain. I.

Description

The invention also relates to pharmaceutically acceptable compositions containing the compounds of the invention and to methods of using the compositions in the treatment of various disorders, including pain.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION BELONGS

I0O1| The invention relates to compounds that can be used as sodium channel inhibitors.

The invention also relates to pharmaceutically acceptable compositions containing the compounds of the invention and to methods of using the compositions in the treatment of various disorders, including pain.

PRIOR ART 0021 Pain is a defense mechanism that allows healthy animals to avoid tissue damage and prevent further damage to affected tissue. However, there are a number of conditions where pain persists beyond its usefulness or where patients may benefit from pain relief. Neuropathic pain is a form of chronic pain caused by damage to sensory nerves (Stage II). ei ai., Ipsidepse gas(ez apa igeaitepi oi peigorainis raip sopaiiopv ip oiye depega! rorshiaiiop. Raip, 2008. 137(3): p. 681-8). Neuropathic pain can be divided into two categories, pain caused by generalized metabolic nerve damage and pain caused by discrete nerve damage. Metabolic neuropathies include postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Indicators of discrete nerve injury include post-amputation pain, post-surgical nerve injury pain, and nerve entrapment injuries similar to neuropathic spinal pain.

I0O3| Voltage-gated sodium (Mach) channels play a critical role in pain signaling. Mau are key biological mediators of electrical signal transmission because they are the primary mediators of rapid action potential increases in many types of excitable cells (eg, neurons, skeletal muscle myocytes, cardiomyocytes). Evidence for the role of these channels in normal physiology, pathological conditions arising from mutations in sodium channel genes, preclinical work on animal models, and the clinical pharmacology of known agents that modulate sodium channels all point to a central role of Mach in the sensation of pain (Kiz5p A. M. apa

Sittipv TV, Raipy! Vezveagsii: Idepiyisayop oi ZtaiI-Moyesshe Ippiryog ilaai Zeyesiiimezu Tagdeiv

Mahmi.8 Bodiit of the SNappeis. My Ipieg/, 2007. 7(4): p. 192-5); Epdiapa 5., MoMade-daiyed driver sNpappe!v: Pe zeagsy og zibiure-z5eiesiime apaidezisv. Ekhrep Orip Ipmezii Ohav 17 (12), r. 1849-64 (2008); Ktaye 0.5. apa Vappop A.MU., Bodipt spappeiv apa posiseriyop: hesepi sopseriv apa

IShegareshis orropiipyev. Sit Orip Rinaptasoi 8 (1), pp. 50-56 (2008)). Mah are the primary mediators of rapid action potential increases in many types of excitable cells (eg, neurons, skeletal muscle myocytes, cardiomyocytes) and are thus critical for the initiation of signal transduction in these cells (NiPe, Vepii, p Spappei5 oi Ehsyarie Metbgapez, Tim ea. (Zipatseg Avzosiagev, Ips., Zipaepapa, MA, 2001)). Because of the role that 27Mau play in the initiation and propagation of neuronal signals, antagonists that reduce Mau currents can prevent or reduce signaling in the nervous system, and Mau channels have long been considered possible targets for reducing pain in hyperexcitable conditions ( Spaiipe M., SNaigeiieg A., Vabisn 0. apa Kgyrr 9.)., Monade-daieid zodiit spappei!5 ip peshgoodisai divogadetv. SM Meshgo! Rizoga Ogyd Tagdeiv 7 (2), p. 144-58 (2008)). Several clinically applicable analgesics have been identified as Mau channel inhibitors. Local anesthetic drugs such as lidocaine block pain by inhibiting Mau channels, and other compounds such as carbamazepine, lamotrigine, and tricyclic antidepressants with proven efficacy in reducing pain are also thought to act by inhibiting sodium channels (Zodegrait

V., Apiisopmiizapiv: azresiv oi Peig tespapivzt5 oi asiop. Yeig U Raip 6 Zirri A, pp. 3-9 (2002); Mapd a.k., Mysney! U. apa Mapa 5.U., Viosk oi regviviepi Iaie Ma" sitepiv Bu apiidergezzapi zepgaiiipe apa ragoheiipe. U. Metrg. Vioi. 222 (2), p. 79-90 (2008)). 004) Mach form a subfamily of the superfamily of potential-dependent ion channels and contain 9 isoforms designated Mau1.1-Mahm1.9.The tissue localization of the nine isoforms varies greatly.

Mach1.4 is the primary sodium channel of skeletal muscle, and Mau1.5 is the primary sodium channel of cardiomyocytes. Mau1.7, 1.8, and 1.9 are predominantly localized in the peripheral nervous system, while Mam1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central and peripheral nervous systems. The functional behavior of the nine isoforms is similar, but differs in the characteristic features of their potential-dependent and kinetic behavior (Saitsegai! UM.A., (zoiYidip A.G. apa Uuakhtap 5.0., IpiegpaiOpa! Opiop oi Ripaptasoyodu.

CHEMISTRY. Motepsiaite apa vigisishge-Ripsiop heiayopePpirv oi moMade-daivd vadisht sNappe!5.

Rpagtasoi Neu. 57 (4), p. 397 (2005)).

IOO5| Immediately after their discovery, Mau1.8 channels were identified as possible targets for analgesia (AKoriap A.M., Bimioni SG. apa Umova .M., A Ieigodoyohip-gezibiapi moiade-daivy 5odiyit spappei ehrgez5z5ey Bu zepzogu pepgop5. Maitsge, 1996. 379 (6562): pp. 257-62). Since then, it has been shown that Mau1.8 is the most significant carrier of the sodium current that supports the excitation of the action potential in small neurons of the eye (Viaig M.T. apa V.R. Veap, Koiez oi iegodoihip (TTX)-

zepeyime Ma sitepi, TTX-hteziviapi Ma" sitepi, apa Sa" sitepi ip She asip roiepiiaI5 oi posiseriime zepvogu peshygop5. U. Meshtsgovzsi., 2002. 22(23): p. 10277-90). Mam1.8 is necessary for spontaneous excitation of damaged neurons, similar to those that cause neuropathic pain (Kola S. ei ai., Te (eigodoiohip-ghteziviapi Ma" snappei! Mami.8 iz ezzepiia! og She ehrgezviop oi 5ropiapeoiz asiimiiu ip datadea 5epzogu ahopz oi tise. .). Rpuzio!., 2003. 550(RI 3): p. 921-6; dagmiv

M.R. ei ai., A-803467, and roiepi apa 5eiIesiime Mam1.8 zodisht spappei riosKeg, ayepiaiie5 peigoraynis apa iptattaiiyogu raip ip Pe gai. Rhos pai! Asai 5si. OBA, 2007. 104(20): p. 8520-5; before 5.K. hey ay.,

Ipmoimetepi oi She TTX-geviviapi zodiit spappei! Maum1.8 ip ipPattaiyogu apa peishgoraiiis, shii poi rozi-oregaiime, raip viaie5. Raip, 2006. 123(1-2): pp. 75-82; And ai u. ei ai., Ippiryiop oi pepgorainis raip

Bu desgeasei ehrgezvsiop oi Pe Ieigodoiyuhip-gevziviiapi zodiit spappei, Mam1,8. Raip, 2002. 95(1-2): pp. 1483-52; Oopud H.M/. hey ayy.,, Come on! ipiepegipd AMA-teaiaey vzeiiIesime KposKdomup oi Ma()1,8

Ieiygodoyyuhip-gezibyapi 5odisht spappe! tgemegze5 tespapisa! ayodupia ip peshoraiyis groves.

Meshgozsiepse, 2007. 146(2): p. 812-21; Nyapo N.G. ei ai., Rgoieotis rgoyipud oi peigotavz hemeai5 anegayopv5 ip rgoivip sotrovyop apa osa! rgoivip zupipevziv ip pureg-ehsiiabiye pegue5. MoiIRaip, 2008. 4: p. 33; ViaskK .A. Yei aI., Mishrie 5odisht sNpappei! isoiopt5 apa tiodep-asiimaivy rgoivyp

Kipazez age rzhezepi ip raipii Nytap peshotav. App Meshgoi, 2008. 64(6): p. 644-53; Somaga K. ei ai.,

Ittypoiosaiigayop oi 5M5/RMZ apa Mam/5M52 zodiyt sNappe!5 ip pitap raiip viaiev. Raip, 2000. 85(1-2): pp. 41-50; Miapdoi U. eyi aI., "M5/RMZ apa 5M52/Mam zodiyt sNappe!-IiKe ittipogeasiimnu ip Nytap adiyiii apa peopaie ipishted zepzogu peguee5. REV5 I ey, 2000. 467(2-3): pp. 249-52; Вяпозвгии

With. moped-dayvd zodisht snappei! 1.8 (Mam1.8) tAMA assitpshayop zsiais pegue ipishgu-ipdysed raiptsh! peshigorainu ip groves 9. Vioi. Spent 286(46): p. 39836-47). Small neurons of the EYE, where Mau1!.8 is expressed, include nociceptors critical for pain signal transmission. Mau1.8 is the primary channel that mediates large-amplitude action potentials in small neurons of the dorsal root ganglia (Viaig M.T. apa Veap V.R., Koye5oi

Ivigodoiyuhip (TTX)-5epeime Ma" sitepi, TTX-geviviapi Ma" sitepi, apa Sa" sitepi ip She asip roiepiyaI (ye oyi posiseriime zepvogu peygop5. Upeshygovsi., 2002. 22(23): p. 10277-90). Mam1.8 is necessary for fast repetitive action potentials in nociceptors and for the spontaneous activity of injured neurons (Spoi 9.5. apa M/akhtap 5.0.

Mam1.7 apa Mau1.8 vadiyit spappeiv: a sotrshiieg vitshinop 5shschau. U. Meigorpusio!. 106(6): p. 3173-

From 84; Vepdapainap M., Sittipv T.V. apa UUMakhtap 5.20., Sopihirshiop oi Ma(x)1.8 vadiyit spappei!5 yuY asiop roiepiya! eIesigodepeviv ip OVS pesygopv. IN). Meshygorpuzio!., 2001. 86(2): p. 629-40; Voga S. eyi aI., Te tiemodoyohip-gezivitapi Ma" spappe! Mau1.8 ie ezzepiya! og She ehrgezviop oi zropiapeoi5 asimpu ip datadei 5epzogu ahop5 oi tise. U. RNuvioi., 2003. 55BO(RIZ): p. 921- 6).. In depolarized or damaged neurons of the OMS, Mam1.8 is apparently the primary stimulator of hyperexcitability (Kyb5yp A.M.

Nuroehsigabiinu ip ayegepi yiurez oi peygop5. Rgos. Mai). Asai. si. OBA, 2006. 103(21): p. 8245-50).

In some animal models of pain, an increase in Mam1.8 mRNA expression levels has been shown in ONCO (byip MU. ei aiI., Vedysey sopashsiip Tayigte oi She taip ahop oi roiuutoda! posiseriime S-Rirhev sopiprshevz o raipits! aiiabeiis peigorainu ip gaiv. Vgaip. 135 (RI2): p. 359-75; ZigisKiapa 1.T. ei ai.,

SPapdez ip pe ehrgevzviop oi Mam1.7, Mami.8 apa Mam!.9 ip a aiviipsi rorshmiaiop oi dogzai gosi dapadiya ippeguaypd Pe gai Kpev ioipi ip a todei oi spgopis ipiattatsogu ioipi raip. Yeishg. U. Raiip., 2008. 12(5): pp. 564-72; Om E. ei ai., Ipsteazeid ehrgezviop oi Ieigodoiohip-geviviapi zodiit spappeiv Mam1.8 apa

Mam1.9 m/ypip dogzai gooi dapaia ip a gai todei oi rope sapseg raip. Meygossy Gay. 512(2): pp. 61-6).

И00О6| The main drawback of known Mau inhibitors is their insufficient therapeutic window, and this is apparently a consequence of their lack of selectivity for isoforms. Because Mam1.8 is predominantly restricted to pain-sensitive neurons, selective Mau1.8 blockers are unlikely to induce the adverse events common to nonselective Mau blockers. Accordingly, there remains a need to develop additional Mau channel antagonists, preferably those that are more selective for Mau!1.8 and more active with increased metabolic stability and fewer side effects.

ESSENCE OF THE INVENTION

I007| It has now been found that the compounds of the present invention and their pharmaceutically acceptable salts and compositions can be used as potential-dependent sodium channel inhibitors. 008) These compounds have the general formula in! in and

N "mn; в в) в в в в в в' And are their pharmaceutically acceptable salts.

I009) These compounds and pharmaceutically acceptable salts and compositions can be used to treat or reduce the severity of a variety of diseases, disorders or conditions, including, but not limited to, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, malignant tumor pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, urinary incontinence or cardiac arrhythmia.

Detailed description of the invention

I0010) In one aspect, the invention relates to compounds of formula I

With a dream

M of them - Y in I or their pharmaceutically acceptable salts, where, independently for each occurrence:

B' represents H, SI, CH3, CE3 or cyclopropyl;

Bg2 is Н, Е, СИ, СМ, СН3, СЕ3 or СНЕ";

ВЗ is Н, Е, СИ, СМ, СЕз, ОСЕз or СЕ2СЕ:»;

B" is H;

IN? is Н, Е, СИ, СН3, OSН3, OSН»СН3, OSНа.СНоСН»: or OSNE»;

VU is Н, Е, СИ, СН3, ОСН3, ОСН».СН3, ОСНа.СНоСН»: or ОСНЕ»;

IN? is H, E or SI;

VU is H, E or Si; and

B" represents Н, Е, СИ, ОСН3, ОСЕ3, ОСНеСН", ОСН(СН33)»г5 or ОСНЕ», provided that Б", В? and EZ at the same time do not represent hydrogen; and that EE, B", Be, Be, and K" are not hydrogen at the same time. 0011) For the purposes of this invention, the chemical elements are designated according to the Periodic Table of Elements, version CA5, Napabook oi spetivzigu apa rpubis5, 757 Ei. In addition, general principles of organic chemistry are described in "Ogdapis Spetivigu", Tpotav zoiteiII, Opimegeiu Zsiepse Vook5,

Zayzaiyo: 1999, and "Magsp" 5 Admapsei Ogdapis Spetivigu", 5 Ei., Ed.: that MV apa Magsy ., dopp

Umieu 5 5op5, Mem! MogK: 2001, the entire contents of which are hereby incorporated by reference. 0012) As described herein, the compounds of the invention may optionally be

Substituted with one or more substituents such as generally illustrated above or as illustrated by specific classes, subclasses and species of the invention. As described herein, variants in formula I include specific groups, for example, such as alkyl and cycloalkyl.

As will be understood by one skilled in the art, the combinations of substituents contemplated by this invention are those combinations which result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that do not change significantly when exposed to conditions that allow their preparation, detection and, preferably, their isolation, purification and use for one or more of the purposes described in this document. In some embodiments, the stable compound or chemically feasible compound is a compound that does not change significantly when stored at 40 C or less, in the absence of moisture or other chemically reactive conditions, for at least one week. 0013) The phrase "optionally substituted" can be used interchangeably with the phrase "substituted or unsubstituted". As a rule, the term "replaced" is preceded by the term

"optional" or not, refers to the replacement of hydrogen radicals in a given structure by a radical of the specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and their examples. Unless otherwise indicated, optionally, a substituted group may have a substituent at each position of the group subject to substitution, and when more than one position in any given structure may be substituted by more than one substituent selected from the specified group, the substituents can be the same or different in each position. A ring substituent, such as heterocycloalkyl, can be linked to another ring, such as cycloalkyl, to form a spiro-bicyclic ring system, for example, both rings share one common atom. As will be understood by one skilled in the art, the combinations of substituents contemplated by this invention are those combinations which result in the formation of stable or chemically feasible compounds. 0014) The phrase "up to" as used herein refers to zero or any integer equal to or less than the number after the phrase. For example, "up to 4" means any 30,1,2, 314. 00151 The terms "aliphatic", "aliphatic group" or "alkyl" as used herein refer to straight chain (ie, unbranched) or branched, a substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units. Unless otherwise indicated, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, the aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, the aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, the aliphatic groups contain 1-6 aliphatic carbon atoms and in other embodiments, the aliphatic groups contain 1-4 aliphatic carbon atoms. Suitable aliphatic groups, as non-limiting examples, include linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups.

I0016| The term "cycloaliphatic" or "cycloalkyl" refers to a monocyclic hydrocarbon ring or a polycyclic hydrocarbon ring system that is fully saturated or contains one or more unsaturated units, but which is not aromatic and has a single point of attachment to another part of the molecule.

I0017| The term "polycyclic cyclic system", as used herein, means

Zo includes bicyclic and tricyclic 4-12-membered structures forming at least two rings, where the two rings have at least one common atom (eg, 2 common atoms), including condensed, bridged or spirocyclic ring systems. 0018) The term "halogen" or "halo" as used herein refers to HE, CI, Hg or I.

І0019| Unless otherwise specified, the terms "heterocycle", "heterocyclyl", "heterocycloaliphatic", "heterocycloalkyl" or "heterocyclic" as used herein refer to non-aromatic, monocyclic, bicyclic or tricyclic ring systems in which one or more ring atoms in one or more ring members is an independently selected heteroatom. A heterocyclic ring may be saturated or may contain one or more unsaturated bonds. In some embodiments, a "heterocycle", "heterocyclyl", "heterocycloaliphatic", "heterocycloalkyl" or "heterocyclic" group has three to fourteen ring members, wherein one or more of the ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen or phosphorus, and each ring in the cyclic system contains from 3 to 7 ring members. 002091 The term "heteroatom" means oxygen, sulphur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulphur, phosphorus or silicon; the quaternized form of any basic nitrogen or a substitutable nitrogen atom from a heterocyclic ring, e.g. M (as in 3,4-dihydro-2H-pyrrolyl), MH (as in pyrrolidinyl), or ME: (as in M-substituted pyrrolidinyl)).

I0021| The term "unsaturated" as used herein means that the group has one or more unsaturated units but is not aromatic. (00221 The term "Alkoxy" or "Thioalkyl" as used herein refers to an alkyl group, as previously defined, attached to the main carbon chain by an oxygen ("Alkoxy") or sulfur ("Thioalkyl") atom. 00231 The term " aryl," used alone or as part of a larger group, as in "aralkyl"? "aralkyl" or "aryloxyalkyl"? refers to monocyclic, bicyclic, and tricyclic ring systems having only five to fourteen ring carbon atoms, where at least one ring in the system is aromatic and wherein each ring in the system contains 3-7 ring carbon atoms.The term "aryl" may be used interchangeably with the term "aryl ring".

(0024) The term "heteroaryl," used alone or as part of a larger group, as in "heteroaralkyl" or "heteroarylalkoxy," refers to monocyclic, bicyclic, and tricyclic ring systems having five to fourteen ring members where at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3-7 ring members. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".

I0025| Unless otherwise stated, structures depicted herein are intended to include all isomeric (eg, enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, configurations K and 5 for each center of asymmetry, isomers (2) and (E) of the double bond and conformational isomers (27) and (E). Thus, individual stereochemical isomers, as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures of these compounds are included in the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. Thus, the scope of the invention includes tautomers of compounds of formula I. Structures also include zwitterionic forms of compounds or salts of formula I, if necessary. (0026) Additionally, unless otherwise stated, it is also intended that structures depicted herein include compounds that differ only in the presence of one or more isotopically enriched or isotopically labeled atoms. Isotopically labeled compounds may have one or more atoms replaced by atoms having the atomic mass or mass number normally found in nature. Examples of isotopes present in compounds of formula I include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, 2H,

ЗН, 196, 170, 15М, 180, 170, 355 and 18. Specific isotopically labeled compounds of formula I, in addition to being used as therapeutic agents, can also be used in drug and/or substrate tissue distribution assays , as analytical tools or as probes in other biological assays. In one aspect of the present invention, tritium (eg, ZN) and carbon-14 (eg, "C") labeled isotopes can be used, taking into account the ease of their detection. In another aspect of the present invention, replacing one or more hydrogen atoms with heavier isotopes such as deuterium (eg, "H") can provide certain

From therapeutic benefits.

I0027)| In one embodiment, the invention relates to a compound of formula I! and related definitions, where K! is H. In another embodiment, K' is SI. In another embodiment, K' is CH3. In another embodiment, K' is a CEz. In another embodiment, K' is cyclopropyl. In another embodiment, K' is H, CEz or SI. In another embodiment, K' is H or SEz.

I0028| In another embodiment, the invention relates to a compound of formula I! and accompanying definitions, where K2 is H. In another embodiment, K2 is PE. In another embodiment of B? is SI. In another embodiment of B? is CM. In another embodiment of K? is SnHz. In another embodiment of K? is

SEz. In another embodiment, K2? is a dream". In another embodiment, K2? is H, SEz or SI. In another version of the implementation of CC? is H or SEz.

I0029| In another embodiment, the invention relates to a compound of formula I! and associated definitions, where the short circuit is H. In another embodiment, the short circuit is PE. In another embodiment, the short circuit is an SI. In another embodiment, the short circuit is a CM. In another embodiment, the short-circuit is a SEz. In another embodiment, the short circuit is a

OS". In another embodiment, the short circuit is a CE2CEz. In another embodiment, the short circuit is H, SEz, SI or OSE»z. In another embodiment, the IVF is H, CEz, or SI.

I0030| In another embodiment, the invention relates to a compound of formula I! and related definitions, where is KE? is N. In another variant of implementation of KE? is EE. In another embodiment of B? is SI. In another embodiment, the KE? is a SNz. In another embodiment of K? is OSnH»h. In another embodiment, EE? is

BASIC In another embodiment, the KE? is OSNaСNoСНz. In another embodiment, the VE" is an OSNE".

I0031| In another embodiment, the invention relates to a compound of formula I! and related definitions, where is EC? is N. In another version of the implementation of CC? is RE. In another version of the implementation of CC? is SI. In another embodiment, Co is CH3. In another embodiment, the short-circuit is an OSnNz. In another embodiment, K5 is

BASIC In another version of BC implementation? is OSNaСNoСНz. In another embodiment, the KE" is an OSNE".

I0032| In another embodiment, the invention relates to a compound of formula I! and accompanying definitions, where KU is H. In another embodiment, K9 is RE. In another embodiment, the EC is an SI. In another embodiment, Pe is H or EC.

I0033| In another embodiment, the invention relates to a compound of formula I! ii of accompanying definitions, where KU represents H. In another version of implementation, KU represents EE. In another embodiment, the EC is an SI. In another embodiment, Pe is H or EC.

I0034| In another embodiment, the invention relates to a compound of the formula! and accompanying definitions, where K/ is H. In another embodiment, K/ is EE. In another embodiment, K" represents SI. In another embodiment, K/" represents OSnH»z. In another embodiment, K" is OSE". In another embodiment, K" is

OSNaSN:I. In another embodiment, KK" is OSN(CH3)r. In another embodiment, K/ is OSNE." In another embodiment, K" is EC, SI, OSH3, or OS. In another embodiment, K" represents E or OSN". (0035) In another aspect, the invention relates to a compound of the formula I-A, or a pharmaceutically acceptable salt thereof, where, independently for each occurrence:

B2 is Е, СИ, СМ, СНз, СЕз or СНЕ"; and

B" represents PE, SI, OSH3, OSE3, OSHn.CH»z, OSH(CH33)»2 or OSNE»P". K? is P. In another embodiment, K2 is CI. In another embodiment, K2 is CM. In another embodiment, K2 is CH3. In another embodiment, K? is CEz. In another embodiment, K? is by myself

SNE."

I0037| In another embodiment, the invention relates to a compound of formula 1-A and accompanying definitions, where KE" is E. In another embodiment, K/ is SI. In another embodiment, K" is OSnH3. In another embodiment, КЕ" represents ОСЕ»z, In another embodiment, B" represents ОСНеСН». In another embodiment, K" is OSN(CH3)". In another embodiment, K" is OSNE".

Зо (0038) In another aspect, the invention relates to a compound of the formula I-B / is i Mne v v / I-B or a pharmaceutically acceptable salt thereof, where, independently for each occurrence:

ВЗ is Е, СИ, СМ, СЕз, ОСЕз or СЕ2СЕ"; and

B" represents P, SI, OSH3, OSH3, OSH»CH3, OSH(CH33)" or OSNE».

I0039) In one embodiment, the invention relates to a compound of formula 1-B and accompanying definitions, where EZ is E. In another embodiment, KZ is SI. In another embodiment, the short circuit is a CM. In another embodiment, the CES is a SEz. In another embodiment, the EZ is an OSE:". In another embodiment, the EZ is a

SES

I0040)| In another embodiment, the invention relates to a compound of formula I-B and related definitions, where K" represents P. In another embodiment, K/ represents SI. In another embodiment, K" represents OSnNaz. In another embodiment, K" is OSE". In another embodiment, K/ is OSNeCH»z. In another embodiment, K" is OSN(CH3)". In another embodiment, K" represents KE, SI, OSNE." In another aspect, the invention relates to a compound of formula 1I-C in ud

Name of I-C or its pharmaceutically acceptable salt, where, independently for each occurrence:

B' represents SI, CH3, CE3 or cyclopropyl;

A: represents Е, СИ, СН3, OSН3, OSНа.СН3, OSНgСНегСН»: or OSNE»; and

B" represents E, CI, OSH3, OSH.CH", OSH(CH33)" or OSNE". (0042) In one of the variants of implementation, the invention relates to the compound of formula 1-C and related definitions, where K' represents SI. In another embodiment, B' is CH3. In another embodiment, K' is CE3. In another embodiment, K' is cyclopropyl. (0043) In another embodiment, the invention relates to a compound of formula I-C and related definitions, wherein EE ? is E. In another embodiment, KE? is SI. In another embodiment, E? is CH. In another embodiment, K? is OSN." In another embodiment, B? is OSNeCH." In another embodiment implementation, K? represents OCH.CHneCH." In another embodiment, E? represents OSNE." (0044) In another embodiment, the invention relates to a compound of formula I-C and associated definitions, where K" represents P. In another embodiment implementation of K/ is SI. In another embodiment, K/ is an OSNz. In another embodiment, K/ is

OSNaSN:I. In another embodiment, КК" is ОСН(СН3)г. In another embodiment, КЕ" is ОСНЕ". (0045) In another aspect, the invention relates to a compound of the formula I-Y 9) in M o

With both; yo

In I-O or its pharmaceutically acceptable salt, where, independently for each occurrence:

IN? represents RE, SI, SM, CHz, SEz or SNE";

A: represents Е, СИ, СН3, OSН3, OSНа.СН3, OSНgСНегСН»: or OSNE»; and

B" represents PE, SI, OSH3, OSE3, OSCHnCH»3, OSH(CH33)" or OSNE". (0046) In one embodiment, the invention relates to a compound of the formula 1-O and accompanying definitions, where K? represents P .

SNR". In another variant of the implementation of the short-circuit: is a SI or SEz.

I0047| In another embodiment, the invention relates to a compound of the formula I-O and associated definitions, where EE? is E. In another variant of implementation of KE? is SI. In another embodiment, IVF is a CH. In another version of EC implementation? is OSnN»z. In another embodiment, the KE? is OSNoSN»z. In another version of EC implementation? is ОСН»оСНоСН». In another embodiment, WITHOUT is ESSENTIAL." In another embodiment, E5 is E, CI, CH3 or OSN. (0048) In another embodiment, the invention relates to a compound of formula I-O and related definitions, where K" represents P. In another embodiment, K/ represents SI. In another embodiment, K" represents OSnNaz. In another embodiment, K" is OSE". In another embodiment, K/ is OSNoCH»z. In another embodiment, K" is OSN(CH3)". In another embodiment, KK" is OSNE." In another embodiment, B" is Е, СИ, OSН3 or ОСЕ:з. (0049) In another aspect, the invention relates to a compound of formula 1I-E

BUT t

KU about its IU or its pharmaceutically acceptable salt, where, independently for each occurrence:

VZ is NE, SI, SM, SEz, OSEz or SES";

IN? is NE, SI, СНз, OSНзи, OSНаСНзи, OSНа.СНеСН" or OSNE;"; and

B" represents P, SI, OSH3, OSH3, OSH»CH3, OSH(CH33)" or OSNE».

I0O50) In one embodiment, the invention relates to a compound of formula 1-E and accompanying definitions, where EZ is E. In another embodiment, KZ is SI. In another embodiment, the short circuit is a CM. In another embodiment, the CU is a SEz. In another embodiment, the short-circuit is an OSE:". In another embodiment, the short circuit is a

Se2Se:z. In another embodiment, EZ is SI, SEz or OSE»z. 0051) In another embodiment, the invention relates to a compound of formula I-E and associated definitions, where K? is R. In another embodiment, Ko is SI. In another embodiment, B" is CH". In another version of EC implementation? is OSnN»z. In another embodiment of B? is OSNeSN". In another embodiment of K? is OSN".SNeSN". In another embodiment, the KE? is OSNE". In another embodiment, BE: is E, SI, CH3 or OSN.

I0052)| In another embodiment, the invention relates to a compound of the formula I-E and accompanying definitions, where KE" is E. In another embodiment, KE" is SI. In another embodiment, K" is OSnNaz. In another embodiment, K" is OSE". In another embodiment, K/ is OSNoCH»z. In another embodiment, K" is OCH(CH3)g". In another embodiment, K/ is OSNE." In another embodiment, ВЕ" is E, SI, OSH3, or ОСЕ3. 0053) In another aspect, the invention relates to a compound of formula 1I-E

Vo and Mr. R

N KI 7 v3

From in/ I-E or its pharmaceutically acceptable salt, where, independently for each occurrence:

B' represents SI, CH3, CE3 or cyclopropyl;

ВЗ is Е, СИ, СМ, СЕз, ОСЕз or СЕ2СЕ"; and

B" represents PE, SI, OSH3, OSE3, OSHnCH»3, OSH(CH33)" or OSNE". (0054) In one of the variants of implementation, the invention relates to a compound of the formula I1-E and accompanying definitions, where K' represents SI In another embodiment, K' is CH3. In another embodiment, K' is CE3. In another embodiment, K' is cyclopropyl. (0055) In another embodiment, the invention relates to a compound of formula I-E and related definitions, where EZ is E. In another variant of implementation, KZ is SI. In another variant of implementation, KZ is CM. In another variant of implementation, KZ is SEz. In another variant of implementation, EZ is OSE:". In another variant of implementation, EZ is

SES

I0056)| In another embodiment, the invention relates to a compound of formula I-E and related definitions, where K" represents P. In another embodiment, K/ represents SI. In another embodiment, EC" represents OSN". In another embodiment, K" represents ОСЕ". In another embodiment, B" represents ОСНеСН". In another embodiment, K" is OSN(CH3)". In another embodiment, K" is OSNE".

I0057| In another aspect, the invention relates to a compound of formula 1-Ci - HerCe

FI N Fmne

What? t of Ia or its pharmaceutically acceptable salt, where, independently for each occurrence:

B: represents P, SI, SM, CHz, SEz or SNE";

VZ is EK, SI, SM, SEz, OSEz or SE»SE;; and

B" represents P, CI, OSH3, OSE3, OSH»CH3, OSH(CH33)" or OSNE". 0058) In one embodiment, the invention relates to a compound of formula 1-5 and related definitions, where K? represents P. In another embodiment, K2 is CI. In another embodiment, K2 is CM. In another embodiment, K2 is CH3. In another embodiment, K? is CEz. In another embodiment, K? is

SNE."

І0059| In another embodiment, the invention relates to a compound of formula 1I- and associated definitions, where KZ is P. In another embodiment, KZ is SI. In another embodiment, the short circuit is a CM. In another embodiment, the short-circuit is a SEz. In another embodiment, the EZ is an OSE:". In another embodiment, the EZ is a

SES 0060) In another embodiment, the invention relates to a compound of formula I-C and accompanying definitions, where KE" is E. In another embodiment, KE" is SI. In another embodiment, K" is OSnNaz. In another embodiment, K" is OSE". In another embodiment, K/ is OSNoCH»z. In another embodiment, K" is OSN(CH3)". In another embodiment, K" is OSNE".

I0061) In another aspect, the invention relates to a compound of the formula I-H p o0 9

H obsmne v3 v5

BU etc

Zo or its pharmaceutically acceptable salt, where, independently for each occurrence:

B' represents SI, CH3, CE3 or cyclopropyl;

ВЗ is Е, СИ, СМ, СЕз, ОСЕз or СЕ2СЕ:";

A: represents Е, СИ, СН3, OSН3, OSНа.СН3, OSНgСНегСН»: or OSNE»; and

B" represents PE, SI, OSH3, OSE3, OSCHnCH»3, OSH(CH33)" or OSNE". (0062) In one of the variants of implementation, the invention relates to a compound of the formula I-H and related definitions, where B' represents SI In another embodiment, B' is CH3 In another embodiment, K' is CE3 In another embodiment, K' is cyclopropyl.

I0063| In another embodiment, the invention relates to a compound of the formula I-H and associated definitions, where EZ is E. In another embodiment, KZ is SI. In another embodiment, the short circuit is a CM. In another embodiment, the CU is a SEz. In another embodiment, the short-circuit is an OSE:". In another embodiment, the short circuit is a

SES

I0064| In another embodiment, the invention relates to a compound of the formula I-H and associated definitions, where K? is R. In another embodiment, Ko is SI. In another embodiment, E? is CH. In another embodiment of K? is OSN»z. In another embodiment of B? is OSNeSN". In another embodiment of K? is OSN".SNeSN". In another embodiment, the RE" is an OSNE". (0065) In another embodiment, the invention relates to a compound of the formula I-H and accompanying definitions, where K" is ER. In another embodiment, KK" is P. In another embodiment, K" is SI. In another embodiment, KE" is OSnNz. In another embodiment, K" is OSE". In another embodiment, K" is

OSNoSNU In another embodiment, K/ represents OSN(CH»z)». In another embodiment, KE" represents OSNE". (0066) In another aspect, the invention relates to a compound of the formula 1-/6) in the o th exchange,

EZ v v o) or its pharmaceutically acceptable salt, where, independently for each occurrence:

B: represents P, SI, SM, CHz, SEz or SNE";

ВЗ is Е, СИ, СМ, СЕз, ОСЕз or СЕ2СЕ:";

A: represents Е, СИ, СН3, OSН3, OSНа.СН3, OSНgСНегСН»: or OSNE»; and

B" is RE, SI, OSN3, OSE3, OSNgCH»z, OSN(СН33)" or OSNE».

I0067| In one of the implementation options, the invention relates to the compound of formula 1-) and accompanying definitions, where K? is P. In another embodiment, K2 is SI. In another embodiment, K2 is a CM. In another embodiment, K2 is CH3. In another embodiment of K? is SEz. In another embodiment of K? is

SNE."

I0068| In another embodiment, the invention relates to a compound of the formula 1-) and accompanying definitions, where EZ is E. In another embodiment, KZ is SI. In another embodiment, the short circuit is a CM. In another embodiment, the short-circuit is a SEz. In another embodiment, the short-circuit is an OSE:". In another embodiment, the short circuit is a

SES

From I0069| In another embodiment, the invention relates to a compound of formula I-) and associated definitions, where K? is R. In another embodiment, Ko is SI. In another embodiment, IVF is a CH. In another version of EC implementation? is OSnN»z. In another embodiment, the KE? is OSNoSN»z. In another embodiment of K? is OSN".SNeSN". In another embodiment, the RE" is an OSNE".

I0070| In another embodiment, the invention relates to a compound of the formula 1-) and accompanying definitions, where KE" represents E. In another embodiment, KE" represents SI. In another embodiment, EK" is an OSN". In another embodiment, K" is an OSE". In another embodiment, "B" is OSNeCH". In another embodiment, K" is OSN(CH3)". In another embodiment, K" represents OSNE".

I0071| In another aspect, the invention relates to a compound of formula 1I-K

M

N V "MN; oh yo

IR or its pharmaceutically acceptable salt, where, independently for each occurrence:

B' represents SI, CH3, CE3 or cyclopropyl; and

IN? is ЕК, СИ, СН3, OSН3, OSНаСНзи, OSНgСНоСН»: or OSNE».

I0072| In another embodiment, the invention relates to a compound of the formula I-K and accompanying definitions, where K' represents SI. In another embodiment, K' is CH3. In another embodiment, K' is a CEz. In another embodiment, K' is cyclopropyl.

I0073| In another embodiment, the invention relates to a compound of formula I-K and associated definitions, where EE? is E. In another variant of implementation of KE? is SI. In another embodiment, E? is CH. In another embodiment of K? is an OSN". In another embodiment of K? is OSNeCH»z. In another embodiment of K? is OSNgSNeSN". In another embodiment, BE: is an OSNE. 0074) In another aspect, the invention relates to a compound of formula I-I. (8; milk

N o "Mne 3 o o in IS or a pharmaceutically acceptable salt thereof, where, independently for each occurrence:

VZ is NE, SI, SM, SEz, OSEz or SES";

VU is E or Si; and

B" represents P, SI, OSH3, OSH3, OSH»CH3, OSH(CH33)" or OSNE».

I0075)| In another embodiment, the invention relates to a compound of formula I-I and associated definitions, where KZ is P. In another embodiment, KZ is SI. In another embodiment, the short circuit is a CM. In another embodiment, the CU is a SEz. In another variant, the implementation of the VZ is an OSE. In another embodiment, the short circuit is a

SES

I0076| In another embodiment, the invention relates to a compound of formula I-I and associated definitions, where KU is E. In another embodiment, EC? is SI.

I0077| In another embodiment, the invention relates to a compound of formula I-I and related definitions, where KE" is E. In another embodiment, KE" is SI. In another embodiment, EK" is an OSN". In another embodiment, K" is an OSE". In another embodiment, "B" is OSNeCH". In another embodiment, K" is OSN(CH3)". In another embodiment, K" represents OSNE". 0078) In another aspect, the invention relates to a compound of the formula I-M 6,

M Ka

N o Mne 3 and, yo

Co., Ltd.) of I-M or its pharmaceutically acceptable salt, where, independently for each occurrence:

ВЗ is Е, СИ, СМ, СЕз, ОСЕз or СЕ2СЕ"; and

IN? is ЕК, СИ, СН3, OSН3, OSНаСНзи, OSНgСНоСН»: or OSNE».

I0079| In another embodiment, the invention relates to a compound of the formula I-M and accompanying definitions, where EZ is E. In another embodiment, KZ is SI. In another embodiment, the short circuit is a CM. In another embodiment, the short-circuit is a SEz. In another embodiment, the EZ is an OSE:". In another embodiment, the EZ is a

SES

I0080| In another embodiment, the invention relates to a compound of the formula I-M and associated definitions, where K? is R. In another embodiment, Ko is SI. In another embodiment, IVF is a CH. In another version of EC implementation? is OSnN»z. In another embodiment, the KE? is OSNoSN»z. In another version of EC implementation? is OSNgSNeSN". In another embodiment, BE: is an OSNE.

I0081) In another aspect, the invention relates to a compound of the formula 1-M o

Fe;

BUT

With (o; ve vo I-M or its pharmaceutically acceptable salt), where, independently for each occurrence:

VZ is NE, SI, SM, SEz, OSEz or SES";

IN? is NE, SI, СНз, OSНзи, OSНаСНзи, OSНа.СНеСН" or OSNE;"; and

Ve is E or SI. (0082) In another embodiment, the invention relates to a compound of the formula I-M and related definitions, where EZ is E. In another embodiment, KZ is SI. In another embodiment, the short circuit is a CM. In another embodiment, the short-circuit is a SEz. In another embodiment, the short circuit is an OSE. In another embodiment, the short circuit is a

SES

I0083| In another embodiment, the invention relates to a compound of the formula I-M and associated definitions, where K? is R. In another embodiment, Ko is SI. In another embodiment, IVF is a CH. In another version of EC implementation? is OSnN»z. In another embodiment, the KE? is OSNoSN»z. In another version of EC implementation? is OSN.SNeSN". In another embodiment, the RE" is an OSNE". (0084) In another embodiment, the invention relates to a compound of the formula I-M and related definitions, where KU is E. In another embodiment, EC? is SI. 0085) In another aspect, the invention relates to a compound of formula 1-0 in o av,

N o Mne in (8; to in Ko) or its pharmaceutically acceptable salt, where, independently for each occurrence:

B' represents SI, CH3, CE3 or cyclopropyl;

VZ is NE, SI, SM, SEz, OSEz or SES";

VU is E or Si; and

B" represents P, SI, OSH3, OSH3, OSH»CH3, OSH(CH33)" or OSNE».

Zo (0086) In another embodiment, the invention relates to a compound of formula 1-0 and accompanying definitions, where K' represents SI. In another embodiment, K' is CH3. In another embodiment, K' is a CEz. In another embodiment, K' is cyclopropyl.

I0087| In another embodiment, the invention relates to a compound of formula 1-O and accompanying definitions, where KZ is P. In another embodiment, KZ is SI. In another embodiment, the short circuit is a CM. In another embodiment, the short-circuit is a SEz. In another embodiment, the EZ is an OSE." In another embodiment, the EZ is a

SES (0088) In another embodiment, the invention relates to a compound of formula 1-O and accompanying definitions, where KU is E. In another embodiment, EC? is SI.

I0089)| In another embodiment, the invention relates to a compound of formula 1-O and accompanying definitions, where K" represents P. In another embodiment, K/ represents SI. In another embodiment, K" represents OSnNaz. In another embodiment, K" is OSE". In another embodiment, K/ is OSNoCH»z. In another embodiment, K" is OSN(CH3)". In another embodiment, K" represents OSNE".

0090) In another embodiment, the invention relates to a compound of formula Y, wherein the compound or a pharmaceutically acceptable salt thereof is selected from Table 1. The names of the compounds in Table 1 were obtained using SpetVioOgamSkga version 12.0 from Satbgidde Zop/Spet Oyise 2010. 00911

Table 1

Numbers, structures and chemical names of compounds

Amendment

And MN we (in) 1 o

LU

CEz 2-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide b, p,

ZU

Co

NM (9)

IS

2 o ke;

IS

SEZ

2-(2,4-difluorophenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide o. ,0 r odes

NM o);

From d

E SEZ

2-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide o, /B

ZU still

NM. yo 'XH,

Yes

THESE

M

2-(2-chloro-4-fluorophenoxy)-4-cyano-M-(3-sulfamoylphenyl)benzamide

Table 1

Numbers, structures and chemical names of compounds

ZY

WITH

НМ about uv

E SI

B-chloro-2-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)benzamide

ОХ ry zu s

E nm (F) b uv

E SEZ

2-(2,4-difluorophenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide o, ,o

B si ni (8; vu

It's sleep

SI

4-chloro-2-(4-rtorphenoxy)-5-methyl-M-(3-sulfamoylphenyl)benzamide 0, ,0

MU

ZU

WITH

NM and and IH,

E SI

Si 4-chloro-2-(2-chloro-4-fluorophenoxy)-M-(3-sulfamoylphenyl)benzamide

Table 1

Numbers, structures and chemical names of compounds

Zm si no) (9) ! THEIR

E SN

These

M

4-cyano-2-(4-fluoro-2-methylphenoxy)-IM-(3-sulfamoylphenyl)benzamide

NM it in

E Osn

THESE

M

4-cyano-2-(4-fluoro-2-methoxyphenoxy)-IM-(3-sulfamoylphenyl)benzamide

Let's go 6)

THEIR,

E SI B

2-(2-chloro-4-fluorophenoxy)-5-cyano-M-(3-sulfamoylphenyl)benzamide

ZU in Me

NM is 12 years old

E SNU

2-(4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide

Table 1

Numbers, structures and chemical names of the compounds of the

With MN

NM (in) 13

SS SEz

E Osn 2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-b-(trifluoromethyl)benzamide in p

ZU

WITH

NM c) 14 uv

E Osn

SEZ

2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide

Oh /V

BU,

With us o o

E -4 Osn

SI

4-chloro-2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide

WITH

(M Mne

NM c) 16

XX,

E Osn" (9

B-chloro-2-(4-fluoro-2-methoxyphenoxy)-IM-(3-sulfamoylphenyl)benzamide

Table 1

Numbers, structures and chemical names of compounds о, / зу (Her and Mne nm (in) 17

SH,

E SI SI

B-chloro-2-(2-chloro-4-fluorophenoxy)-M-(3-sulfamoylphenyl)benzamide

So" nm (in) 18 in!

LJ

SEZ

2-(4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide

In s nm (6) 19 o

HK

(o 4-chloro-2-(4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)benzamide 0, ,0

MU

ZU

And many nm (in; uv

E SN SI

B-chloro-2-(4-fluoro-2-methylphenoxy)-IM-(3-sulfamoylphenyl)benzamide

Table 1

Numbers, structures and chemical names of compounds 00.0 re p

NM at 9 p.m

THEIR,

E " SN E

B-fluoro-2-(4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)benzamide 9.0 a

С МН» ko (o) 22 uva neo SEZ 2-(4-methoxyphenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide o, 0

XX

ZU

With Mn; nm at 11 p.m

EU SEZ

2-(4-ethoxyphenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide

ZU

Di

NM. o and that in all SEZ 2-(4-chlorophenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide

Table 1

Numbers, structures and chemical names of the compounds of the mon sl

C Mn» sn nm o

WITH

E SEZ

2-(4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide

E SEZ

2-(2-chloro-4-fluorophenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide

Oh /

ZU

Sleep

Os nu i) 27 Nz sg

E SEZ

2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-

B-(trifluoromethyl)benzamide 0. ,0

MU

ZU

НМ 6) 28 вв шк) SEZ 2-(3-fluoro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)-

B-(trifluoromethyl)benzamide

Table 1

Numbers, structures and chemical names of compounds 0.0 p

Sleep (in) 29 Mon

SEZ

2-(3-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-

B-(trifluoromethyl)benzamide o, ,0

MU

ZU

With sn shk! (o) 30 Z y

SI SEZ

2-(4-chloro-2-methylphenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide

With still 6)

ССИ nНзсо СЕз 2-(2-chloro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)-

B-(trifluoromethyl)benzamide 9, ,0

MU zu

Her and MN"

НМ (6) 32 СНз

Su and

SEZ

M-(3-sulfamoylphenyl)-2-(O-tolyloxy)-5-(trifluoromethyl)benzamide

Table 1

Numbers, structures, and chemical names of compounds about ra

ZU

(In MN"

NM 6)

IS

2-(2-chloro-4-fluorophenoxy)-M-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide 0, ,0

MU zu (in MN"

NM (in) from 4 Osn"

Sg

SEZ

2-(2-Methoxyphenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamido, ra 5,

Ii Z MN"

NM (F;

ZB Osn" sg

SI SEz 2-(4-chloro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-

B-(trifluoromethyl)benzamide o, /B

ZU

With MN

NI (c) 36 Osn» with nzoso SEZ 2-(2,4-dimethoxyphenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide

Table 1

Numbers, structures and chemical names of compounds

Amendment

You are c) 37

WITH

ХА, SEZ 2-(4-isopropoxyphenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide o, /В зх ( M Mne

NM c) 38 SI

IS

2-(2-chloro-4-fluorophenoxy)-6-methyl-N-(3-sulfamoylphenyl)benzamide

Ou r

ХХ

(M Mne

NM c) 39 d

EzZSO SEZ

M-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide

With MN"

NM (8,

SI

40 su

IS

IS

IS

2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-M-(3-sulfamoylphenyl)benzamide

Table 1

Numbers, structures and chemical names of compounds

ZU

Son nyu i) m Ye o; in addition, 2-(4-(difluoromethoxy)phenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide o, p

ZU

With MN

NI i) osn" 42 p

SI

CEz 2-(4-chloro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide

Ex

WITH

NM (o)

Ying Ko:o)

SEZ

2-(3-fluoro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide b, /

ZU

With Mn

NM (6)

Osn 44 Ge!

SEZ

2-(2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide

Table 1

Numbers, structures and chemical names of the compounds of the

With MN"

NM (in) 45 o

EU and

CEz 2-(4-ethoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide 9, ,0

MU zu

With MN

NM about fi 46 su

SEZ

2-(2-propoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide

WITH

Co

NM (9,

Sleep; 47 | at

SEz

M-(3-sulfamoylphenyl)-2-(O-tolyloxy)-4-(trifluoromethyl)benzamide

NM about

SI nzso

SEZ

2-(2-chloro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide

Table 1

Numbers, structures and chemical names of compounds

LLC in MN"

NM (8)

SNnz 49 s nchesO

SEZ

2-(4-methoxy-2-methylphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide borax

ZU

With Mn"

NM c)

Basic

Because Su no

CEz 2-(2,4-dimethoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide o, 28

Зх ( In MN"

NM (c) 51 (F)

EZSO" Fr

SE»z

M-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide

Oh, 0 years

Co

NM (c)

Osn 52 k 7 ke;

SEZ

2-(3-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide

Table 1

Numbers, structures and chemical names of compounds

Go out

NM and -

CEz 2-(4-isopropoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide o, / zu ( With МНо nm o)

Osn"

Bachelor of Arts

IS

OSEz 2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide

Oh,,0 r (From MN"

NM 6) Fr

E" Z

OSEz 2-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide

Оу /В зу

And to me

NM (c);

SI

56 (about)

IS

ОСЕ»z 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide

Table 1

Numbers, structures and chemical names of compounds

WITH

And in MN"

НМ (6) 97 Osn» su CEz 2-(2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamid o, 0 row units) 58 CHz

SI

2-(4-chloro-2-methylphenoxy)-M-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide

Oh in

ZU

Wed

НМ (c) 59 СНз ни СЕз 2-(3-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide o, rai

ZU

WITH

Niyu c) because in SEz

EZSO

M-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)benzamide

Table 1

Numbers, structures and chemical names of compounds

With co

НО 61 in SEZ neo 2-(3-fluoro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)-b-(trifluoromethyl)benzamide

Ba ( In MN" we in) si 62 | oh but

OSEz 2-(2-chloro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide

ZU

WITH

NM. YO si - 63 o

ОСЕ»z 2-(2-chlorophenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide 0, ,0

ZI in MN" and

Well noo

E (9) 64 | at

ОСЕz 2-(2-(difluoromethoxy)phenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide

Table 1

Numbers, structures and chemical names of compounds

From in MN

NM (c)

Osn 65 su

SI

OS» 2-(4-chloro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide

Oh,/8

ZU

And MN"

NM (c)

Monday post

OSEz 2-(3-chloro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide o, 8

Зх (А МН» ни) 67 in no

SEZ

2-(3-chloro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide

Zu

НМ i) вв осн

CEz 2-(3-chloro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide

Table 1

Numbers, structures and chemical names of compounds

WITH

With MN"

NM about

IS

IS

ES OTE

2-(4-fluorophenoxy)-4-(perfluoroethyl)-M-(3-sulfamoylphenyl)benzamide 05.8

ZU

With Mn"

NM. yo

Osn" 70 o

IS

IS

EZSTOTE

2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-M-(3-sulfamoylphenyl)benzamide va v, Mn»

NM (c)

Osn: 71 Z rev)

SI

IS

EZS7 TE 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-M-(3-sulfamoylphenyl)benzamide 9.8

ЗМ в, МН ни (Ф) (Fi

ShK eo) E

EZS7OTE 2-(2-chloro-4-methoxyphenoxy)-4-(perfluoroethyl)-M-(3-sulfamoylphenyl)benzamide

Zo

Table 1

Numbers, structures and chemical names of compounds o, ,0 r

And MN"

NM (F)

SI

73 | at

SE» 2-(2-chlorophenoxy)-M-(3-sulfamoylphenyl)-4- (trifluoromethyl)benzamide vd c, Mn» ni c) 74 SI sg SEZ 2-(2-chlorophenoxy)-M-(3-sulfamoylphenyl) )-6-(trifluoromethyl)benzamide

ZU

She is in MN"

НМ (о) с СЕз nНсо 2-(2-chloro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)-b-(trifluoromethyl)benzamide o,

ZU in, MN"

NM (c)

Osn 76 | oh but SI

SI

4,5-dichloro-2-(2,4-dimethoxyphenoxy)-IM-(3-sulfamoylphenyl)benzamide

Table 1

Numbers, structures and chemical names of compounds

With in, Mn

NM (9)

Osn 77 | at

E SI

SI

4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide

And a lot (9) 78 o

E - SI

SI

4,5-dichloro-2-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)benzamide

Oh /V

ZU

And Mne nim 6) 79 And about Ko; but SI

SI

4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide o, /B

ZU

And with MN"

NM (c)

Osn" 80 | is)

SI SI

SI

4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide

Table 1

Numbers, structures and chemical names of the compounds of the

With Mo

NM. at

E nHzso SI si 4,5-dichloro-2-(2-fluoro-4-methoxyphenoxy)-M-(3- sulfamoylphenyl)benzamide o, /B zu

С МН» nm () si 82 | about nNzsO SI

IF

4,5-dichloro-2-(2-chloro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamido o, ra

ZM in, MN"

NM and)

SNz 83 o

E SI

SI

4,5-dichloro-2-(4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)benzamide o, "B

ZU in, Mne

NM (F)

OSN" with nso

SI

4-chloro-2-(2,4-dimethoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide

Table 1

Numbers, structures and chemical names of compounds

From the to me

Co.)

Osn 85 | at

SI

SI

4-chloro-2-(4-chloro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide

With in, MN

NM (c)

SI

86 ate) o)

SI

4-chloro-2-(2-chloro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide bu / in in:

MN"

NM at 87 Ge) ro c

SI

4-chloro-2-(4-isopropoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide o, /

ZU in MN shk (F) 88 /vY SEz

IS

SEZ

2-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide

Table 1

Numbers, structures and chemical names of compounds 04.0 r in Mn»ny (0)

Osn 89 o Ko) SEZ

IS

SEZ

2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide

I r MN"

NM o); 90 o) SEZ

BUT in

E SEZ

2-(3-fluoro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide o, ,0

With MN"

NM (F)

IS

91 C SE nzso

SEZ

2-(2-fluoro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide b, p:

With Mn"

NM (6) OSN 92 - Fr. ; SEZ

E SEZ

2-(5-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide

Table 1

Numbers, structures and chemical names of compounds a

With UMN

Kf) sleep 93 o Ko; SEZ

IS

CEz 2-(4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide vd

С МНь ни c) 94 С SI

IS

SI

2,4-dichloro-6-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)benzamide 9.0 g

Ex

And Mn" nu (c)

Osn" 95 p. c

IS

SI

2,4-dichloro-6-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide 0.00 ra

With many nm (0)

SNz 96 about He Si

IS

SI

2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide

Coll

Table 1

Numbers, structures and chemical names of compounds

Zshch

With Mn"

NM and

2,4-dichloro-M-(3-sulfamoylphenyl)-6-(4-(trifluoromethoxy)phenoxy)benzamide

ZI,

And Mn"

NM (c) basic 98 su SI

SI

SI

2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide 0.0 "y p:

With Mn"

NM (6)

E nzso

SI

2,4-dichloro-6-(2-fluoro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide o, /B

ZU

(M MN"

NM 6) 100 o

NS;

E SEZ

2-cyclopropyl-6-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide

I0092| In one embodiment, the compound is 2-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide or its pharmaceutically acceptable salt.

II0093| In another embodiment, the compound is 2-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

I0094| In another embodiment, the compound is 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

II0095| In another embodiment, the compound is 2-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

I0096| In another embodiment, the compound is 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

I0097| In another embodiment, the compound is 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-M-(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is 2-(4-fluorophenoxy)-4-(perfluoroethyl)-M-(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable salt thereof.

I0099| In another embodiment, the compound is 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-M-(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable salt thereof. 00100) In another embodiment, the compound is 2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

ИО0О101| In another embodiment, the compound is 5-chloro-2-(4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable salt thereof.

II00102| In another embodiment, the compound is 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable salt thereof.

ИЙО0103| In another embodiment, the compound is 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable salt thereof.

II00104| In another embodiment, the compound is 2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable salt thereof. 00105) In another embodiment, the compound is 2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

Zo 00106) In another embodiment, the compound is 2-(4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

ЙО0107| In another embodiment, the compound is 5-chloro-2-(2-chloro-4-fluorophenoxy)-M-(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable salt thereof. 00108) In another embodiment, the compound is 2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide or a pharmaceutically acceptable salt thereof. 00109) In another embodiment, the compound is 2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof. 00110) In another embodiment, the compound is 4,5-dichloro-2-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable salt thereof. 00111) In another embodiment, the compound is 2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-M-(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable salt thereof.

II00112| In another embodiment, the compound is 5-fluoro-2-(4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable salt thereof. 00113) In another embodiment, the compound is 2-(2-chloro-4-fluorophenoxy)-4-cyano-M-(3-sulfamoylphenyl)benzamide or a pharmaceutically acceptable salt thereof. 00114) In another embodiment, the compound is M-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide.

Salts, compositions, application, composition, introduction and additional means

Pharmaceutically Acceptable Salts and Compositions 00115) As discussed herein, the invention relates to compounds that are voltage-gated sodium channel inhibitors, and thus the compounds can be used to treat diseases, disorders, and conditions, including, but not limited to, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, malignant tumor pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, urinary incontinence or cardiac arrhythmia. Accordingly, in another aspect, the invention relates to pharmaceutically acceptable compositions, wherein said compositions contain any of the compounds as described herein, and optionally contain a pharmaceutically acceptable carrier, excipient, or binder. In certain embodiments, these compositions optionally additionally contain one or more additional therapeutic agents. In another embodiment, the invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or binders. (00116) It should also be understood that certain of the compounds of the invention may exist in free form for treatment or, if necessary, in the form of a pharmaceutically acceptable derivative thereof.

According to the invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which, when administered to a subject in need thereof, is capable of providing, directly or indirectly, a compound such as otherwise described herein, or its metabolite or residue.

I00117| As used herein, the term "pharmaceutically acceptable salt" refers to those salts which, within the framework of sound medical judgment, are suitable for use in contact with human and lower animal tissues, without excessive toxicity, irritation, allergic reaction, etc., and corresponding to a reasonable benefit/risk ratio. "Pharmaceutically acceptable salt" refers to any non-toxic salt or ester salt of a compound of the present invention which, when administered to a recipient, is capable of providing, directly or indirectly, a compound of the present invention or a metabolite or residue thereof with inhibitory activity. As used herein, the term "its metabolite or residue with inhibitory activity" means that its metabolite or residue is also a voltage-gated sodium channel inhibitor. 00118) Pharmaceutically acceptable salts are well known in the art. For example, Vegde 5.M. her aI. describe in detail the pharmaceutically acceptable salts in 3. Rnaptaseshisa! 5siepsevs, 1977, 66, 1-19, the content of which is incorporated in this document as a reference. Pharmaceutically acceptable salts of the compounds of this invention include salts obtained from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are amino group salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or using other methods used in the art, such as ion exchange. Others

Pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, iodohydrate, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, Z-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and M'U (C-4alkyl) l. The present invention also contemplates the quaternization of any nitrogen-containing basic groups from the compounds described herein. Products that are soluble or dispersible in water or oil can be prepared by such quaternization. Representative salts of alkali or alkaline earth metals include sodium, lithium, potassium, calcium, magnesium, etc. Additional pharmaceutically acceptable salts include, if necessary, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide , carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. 00119) As described herein, the pharmaceutically acceptable compositions of the invention further comprise a pharmaceutically acceptable carrier, adjuvant, or binder, which, as used herein, includes all solvents, diluents, or other liquid binders that facilitate dispersion or suspending agents, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., which are suitable for the particular desired dosage form.

In Vetipdiopye Rpaptaseshisa! Zsiepse5, bihieepii Eyiiop, E. MU. Mapip (Mask Rybiibnipa So.,

Easiop, Ra., 1980) described various carriers used for the preparation of pharmaceutically acceptable compositions, and known methods of their preparation. Except in cases where any generally accepted carrier medium is incompatible with the compounds of the invention, for example, by imparting some undesirable biological action or otherwise interacting adversely with any other component(s) of the pharmaceutically acceptable composition, it is contemplated that its use is included in the scope of this invention. Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchange agents, aluminum oxide, aluminum stearate, lecithin, whey proteins such as human serum albumin, buffering agents such as phosphates, glycine, sorbic acid or potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disubstituted sodium phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, block- copolymers of polyethylene and polyoxypropylene, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; fillers such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogenic water; isotonic saline solution; Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and colors, release agents, coating agents, sweeteners, flavoring agents, preservatives and antioxidants may also be present in the composition, according to the composer's judgment. (00120) In another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.

I00121| In another aspect, the invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof from the compounds of formula I and one or more pharmaceutically acceptable carriers or binders.

Use of compounds and pharmaceutically acceptable salts and compositions

I00122| In another aspect, the invention relates to a method of inhibiting a potential-dependent sodium channel in a subject, which includes administering to the subject a compound of formula I! or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In another aspect, the voltage-gated sodium channel is Mam1.8. 00123) In yet another aspect, the invention relates to a method of treating or alleviating the severity of

Co) of a subject with chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, malignant tumor pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, urinary incontinence or arrhythmia of the heart, which includes the administration of an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of compounds of formula Y. (00124) In another aspect, the invention relates to a method of treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, bone- muscle pain, acute pain, inflammatory pain, malignant tumor pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, urinary incontinence or cardiac arrhythmia, which comprises administering an effective amount of the compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition with compounds of formula I. 00125) In yet another aspect, the invention relates to a method of treating or reducing the severity of intestinal pain in a subject, where pain in shingles includes pain in inflammatory bowel disease, pain in Crohn's disease, or pain in interstitial cystitis. 00126) In yet another aspect, the invention relates to a method of treating or alleviating neuropathic pain in a subject, wherein the neuropathic pain includes postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton's neuroma; injury with pinched nerve, spinal stenosis, carpal tunnel syndrome, sciatica, sciatica; injury with rupture of the nerve, injury with rupture of the brachial plexus; complex regional pain syndrome, neuralgia induced by drug therapy, neuralgia induced by chemotherapy of a malignant tumor, neuralgia induced by therapy against retroviruses; pain after spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic cephalgia.

I00127| In yet another aspect, the invention relates to a method of treating or reducing the severity of musculoskeletal pain in a subject, wherein the musculoskeletal pain includes osteoarthritis pain, spinal pain, cold pain, burn pain, or tooth pain. 00128) In yet another aspect, the invention relates to a method of treating or reducing the severity of idiopathic pain in a subject, wherein the idiopathic pain includes fibromyalgia pain.

00129) In yet another aspect, the invention relates to a method of treating or reducing the severity of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain or vulvodynia. 00130) In yet another aspect, the invention relates to a method of treating or alleviating chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, malignant tumor pain, idiopathic pain, multiple sclerosis in a subject. , Charcot-Marie-Tooth syndrome, urinary incontinence, or cardiac arrhythmia, which involves the administration of an effective amount of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the compounds of the formula | with one or more additional therapeutic agents administered during, before or after treatment with the compound or pharmaceutical composition. 00131) In yet another aspect, the invention relates to a method of treating or reducing the severity of intestinal pain in a subject, wherein the intestinal pain comprises inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain, wherein said method comprises administering an effective amount of a compound , a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of compounds of formula I. 00132) In yet another aspect, the invention relates to a method of treating or reducing the severity of neuropathic pain in a subject, wherein the neuropathic pain includes postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, pain after amputation, phantom pain, painful neuroma; traumatic neuroma; Morton's neuroma; injury with pinched nerve, spinal stenosis, carpal tunnel syndrome, sciatica, sciatica; injury with rupture of the nerve, injury with rupture of the brachial plexus; complex regional pain syndrome, neuralgia induced by drug therapy, neuralgia induced by chemotherapy of a malignant tumor, neuralgia induced by therapy against retroviruses; pain after spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic cephalgia, wherein said method comprises administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of compounds of formula I.

Zo 00133) In yet another aspect, the invention relates to a method of treating or reducing the severity of musculoskeletal pain in a subject, wherein the musculoskeletal pain includes osteoarthritis pain, spinal pain, cold pain, burn pain, or tooth pain , wherein said method includes administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of compounds of formula I. 00134) In yet another aspect, the invention relates to a method of treating or reducing the severity of inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain or vulvodynia, wherein said method comprises administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of compounds of formula I. 00135) In yet another aspect, the invention relates to a method of treating or alleviating the severity of idiopathic pain in a subject, wherein idiopathic pain includes pain in fibromyalgia, wherein said method includes the administration of an effective amount of the compound, its pharmacists of an acceptable salt or pharmaceutical composition of the compounds of formula I. 00136) In yet another aspect, the invention relates to a method wherein the subject is treated with one or more additional therapeutic agents that are administered during, before, or after treatment with an effective amount of the compound, its fPharmaceutically acceptable salt or pharmaceutical composition of compounds of formula I.

І00137| In another aspect, the invention relates to a method of inhibiting a potential-dependent sodium channel in a subject, which includes administering to the subject an effective amount of a compound, its pharmaceutically acceptable salt or a pharmaceutical composition of compounds of formula I. In another aspect, the potential-dependent sodium channel is Mam1.8.

I00138| In another aspect, the invention relates to a method of inhibiting a potential-dependent sodium channel in a biological sample, which includes bringing the biological sample into contact with an effective amount of a compound, its pharmaceutically acceptable salt, or a pharmaceutical composition of compounds of formula I. In another aspect, the potential-dependent sodium channel is Mam!1.8. (00139) In another aspect, the invention relates to a method of treating or reducing the severity in a subject of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy, epileptic conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders,

neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, urinary incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, sciatica, sciatica, spinal pain, headache, neck pain, severe pain, chronic pain, nociceptive pain, sudden sharp pain, post-surgical pain, malignant tumor pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension or abnormal gastrointestinal motility, which includes the administration of an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of compounds of formula I. 00140) In another aspect, the invention relates to a method of treating or reducing the severity of pain in a subject due to a malignant tumor of the femur; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic pain in the lower back; myofascial pain syndrome; fibromyalgia; dysfunctional-pain syndrome of the temporomandibular joint; chronic visceral pain, abdominal pain; pain in the pancreas; pain at IV5; chronic and acute headache; migraines; tension headaches, cluster headaches; chronic and acute neuropathic pain, postherpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensory neuropathies; peripheral nerve damage; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiation therapy-induced neuropathic pain; pain after mastectomy; central pain; pain in case of spinal cord injury; pain after a stroke; thalamic pain; complex regional pain syndrome; phantom pain; chronic pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical pain in the lower back; neck pain; tendinitis; pain in case of injury; pain during physical exertion; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, heart pain; pelvic pain, pain with renal annulus, acute pain during pregnancy, labor cramps; pain during cesarean section; sharp pain

With inflammation, burn and injury; acute periodic pain, endometriosis; acute pain in shingles; sickle cell anemia; acute pancreatitis; sudden sharp pain; orofacial pain, including sinusitis pain, toothache; pain in multiple sclerosis (M5); pain in depression; pain in leprosy; pain in Behcet's disease; adiposaliiy; pain in phlebitis; pain in Guillain-Barré syndrome; painful movements of the legs and fingers; Hoglund's syndrome; pain in erythromelalia; pain in Fabry disease; diseases of the urinary bladder and genitourinary disorders, including urinary incontinence; bladder hyperactivity; painful bladder syndrome; interstitial cystitis (IS); prostatitis; complex regional pain syndrome (CRP), type I and type II; generalized pain, paroxysmal extremity pain, pruritus, tinnitus, or angina-induced pain, which involves the administration of an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of compounds of formula I. 00141) In another aspect, the invention relates to a method of treating or alleviating the severity of sub neuropathic pain agent, which comprises administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of compounds of formula I. In one aspect, the neuropathic pain is selected from postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning syndrome mouth, pain after amputation, phantom pain, painful neuroma, traumatic neuroma; Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, sciatica, sciatica, nerve laceration injury, brachial plexus laceration injury, complex regional pain syndrome, drug-induced neuralgia, chemotherapy-induced neuralgia malignancy, neuralgia induced by antiretroviral therapy, pain after spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic cephalgia.

Preparation of medicinal products 00142) In one aspect, the invention relates to the use of a compound or pharmaceutical composition described herein for the preparation of a medicinal product for use in the inhibition of a potential-dependent sodium channel. In another aspect, the voltage-gated sodium channel is Mam1.8.

00143) In yet another aspect, the invention relates to the use of a compound or pharmaceutical composition described herein for the preparation of a medicament for use in treating or alleviating a subject's chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, malignant tumor pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, urinary incontinence or cardiac arrhythmia. 00144) In yet another aspect, the invention relates to the use of a compound or pharmaceutical composition described herein for the preparation of a medicament for use in the treatment or alleviation of bowel pain in a subject, wherein the bowel pain includes inflammatory bowel disease pain, Crohn's disease or pain in interstitial cystitis. 00145) In yet another aspect, the invention relates to the use of a compound or pharmaceutical composition described herein for the preparation of a medicament for use in the treatment or alleviation of neuropathic pain in a subject, wherein the neuropathic pain includes postherpetic neuralgia, diabetic neuralgia, painful HIV-associated neuralgia sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, pain after amputation, phantom pain, painful neuroma, traumatic neuroma; neuroma

Morton; injury with pinched nerve, spinal stenosis, carpal tunnel syndrome, sciatica, sciatica; injury with rupture of the nerve, injury with rupture of the brachial plexus; complex regional pain syndrome, neuralgia induced by drug therapy, neuralgia induced by chemotherapy of a malignant tumor, neuralgia induced by therapy against retroviruses; pain after spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic cephalgia. 00146) In yet another aspect, the invention relates to the use of a compound or pharmaceutical composition described herein for the preparation of a medicament for use in the treatment or alleviation of musculoskeletal pain in a subject, wherein the musculoskeletal pain includes pain in osteoarthritis, spinal pain, cold pain, burn pain or toothache.

From I00147| In yet another aspect, the invention relates to the use of a compound or pharmaceutical composition described herein for the preparation of a medicament for use in treating or alleviating inflammatory pain in a subject, wherein the inflammatory pain includes rheumatoid arthritis pain or vulvodynia. 00148) In yet another aspect, the invention relates to the use of a compound or pharmaceutical composition described herein to provide a medicament for use in the treatment or alleviation of idiopathic pain in a subject, wherein the idiopathic pain includes fibromyalgia pain. 00149) In yet another aspect, the invention relates to the use of a compound or pharmaceutical composition described herein for the preparation of a medicinal product in combination with one or more additional therapeutic agents administered during, before or after treatment with the compound or pharmaceutical composition. 00150) In another aspect, the invention relates to the use of a compound or pharmaceutical composition described herein for the preparation of a medicament for use in the treatment or alleviation of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia nerve, herpetic neuralgia, generalized neuralgia, epilepsy, epileptic states, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, urinary incontinence, visceral pain , pain in osteoarthritis, postherpetic neuralgia, diabetic neuropathy, sciatica, sciatica, spinal pain, headache, neck pain, severe pain, chronic pain, nociceptive pain, sudden sharp pain, postsurgical pain, pain in malignant tumor, stroke, ischemia brain injury traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility. 00151) In another aspect, the invention relates to the use of a compound or pharmaceutical composition described herein for the preparation of a medicinal product for use in the treatment or alleviation of pain due to a malignant tumor of the femur; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic pain in the lower back; myofascial pain syndrome;

fibromyalgia; dysfunctional-pain syndrome of the temporomandibular joint; chronic visceral pain, abdominal pain; pain in the pancreas; pain at IV5; chronic and acute headache; migraines; tension headaches, including cluster headaches; chronic and acute neuropathic pain, postherpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie neuropathy

Tuta; hereditary sensory neuropathies; peripheral nerve damage; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy-induced neuropathic pain; radiation therapy-induced neuropathic pain; pain after mastectomy; central pain; pain in case of spinal cord injury; pain after a stroke; thalamic pain; complex regional pain syndrome; phantom pain; chronic pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical pain in the lower back; neck pain; tendinitis; pain due to injury/physical stress; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, heart pain; pelvic pain, pain with renal annulus, acute pain during pregnancy, labor cramps; pain during cesarean section; acute pain during inflammation, burn and injury; acute periodic pain, endometriosis; acute pain in shingles; sickle cell anemia; acute pancreatitis; sudden sharp pain; orofacial pain, including sinusitis pain, toothache; pain in multiple sclerosis (M5); pain in depression; pain in leprosy; pain in Behcet's disease; adiposalgia; pain in phlebitis; pain in Guillain-Barré syndrome; painful movements of the legs and fingers; Hoglund's syndrome; pain in erythromelalgia; pain during illness

Fabri; diseases of the urinary bladder and genitourinary disorders, including urinary incontinence; bladder hyperactivity; painful bladder syndrome; interstitial cystitis (IS); prostatitis; complex regional pain syndrome (CRPS), type I and type II; generalized pain, paroxysmal limb pain, pruritus, tinnitus or angina-induced pain. 00152) In another aspect, the invention relates to the use of a compound or pharmaceutical composition described herein for the preparation of a medicinal product for use in the treatment or alleviation of neuropathic pain. In one aspect

Neuropathic pain is selected from postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, neuroma

Morton's nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, sciatica, sciatica, nerve laceration injury, brachial plexus laceration injury, complex regional pain syndrome, drug-induced neuralgia, chemotherapy-induced neuralgia of malignancy tumors, antiretroviral therapy-induced neuralgia, pain after spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic cephalgia.

Administration of Pharmaceutically Acceptable Salts and Compositions 00153) In certain embodiments, an "effective amount" of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition is an amount effective to treat or reduce the severity of one or more of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, pain from a malignant tumor, idiopathic pain, multiple sclerosis, Charcot-Marie syndrome

Tuta, urinary incontinence or cardiac arrhythmia.

І00154| The compounds and compositions according to the method of the invention can be administered using any amount and any method of administration effective to treat or reduce the severity of one or more of the pain or non-pain conditions listed herein. The exact amount required may vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the specific agent, the method of its administration, etc. The compounds of the invention are preferably formulated in a standard dosage form for ease of administration and uniformity of dosage. The term "standard dosage form" as used herein refers to a physically discrete unit of agent suitable for the subject to be treated. However, it should be understood that with regard to the general daily use of the compounds and compositions according to the invention, the attending physician makes a decision within the framework of sound medical judgment. The particular effective dosage level for any particular subject or organism depends on a variety of factors, including the disorder being treated and the severity of the disorder; activity of the specific compound used; specific applied composition; age, body weight, general health, gender and diet of the subject; the time of introduction, the method of introduction and the rate of removal of the specific compound used; duration of treatment; drugs used in combination or with the particular compound used and similar factors well known in the medical field. The term "subject" or "patient" as used herein refers to an animal, preferably a mammal and most preferably a human. 00155) Pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), buccally as by oral or nasal spray or the like. n., depending on the severity of the infection to be treated. In certain embodiments, the compounds of the invention can be administered orally or parenterally at dosage levels of from about 0.01 mg/kg to about 50 mg/kg, and preferably from about 1 mg/kg to about 25 mg/kg body weight of a subject per day , one or more times a day, to obtain the desired therapeutic effect. 00156) Liquid dosage forms for oral administration include, as non-limiting examples, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents generally accepted in the art, for example, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol . In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, and flavoring agents.

I00157| Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be formulated in accordance with the known art using suitable dispersing or wetting agents and suspending agents. A sterile injectable preparation can also be a sterile injectable

A solution, suspension or emulsion in a non-toxic diluent or solvent suitable for parenteral administration, for example, such as a solution in 1,3-butanediol. Acceptable carriers and solvents that can be used include water, Ringer's solution, 0.5. R. and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are generally accepted as a solvent or suspending medium. Any tasteless non-volatile oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable preparations.

I00158| Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by including sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

I00159| To prolong the effect of the compounds of the invention, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be done by using a liquid suspension of crystalline or amorphous material with poor solubility in water. Then the rate of absorption of the compound depends on the rate of its dissolution, which, in turn, may depend on the size of the crystals and the crystalline form. Alternatively, delayed absorption of the parenterally administered form of the compound is accomplished by dissolving or suspending the compound in an oil carrier. Injectable depot forms are obtained by forming matrices of microcapsules of compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the nature of the specific polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoethers) and poly(anhydrides). Depot compositions suitable for injection are also obtained by entrapping the compound with liposomes or microemulsions compatible with body tissues. 00160) Compositions for rectal or vaginal administration are preferably suppositories which may be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or suppository wax which are solid at ambient temperature but liquid at body temperature and thus melt in the cavity of the rectum or vagina and 60 release the active compound.

00161) Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or calcium diphosphate, and/or a) excipients or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid, B) with binding agents, for example, such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and gum arabic, c) with humectants, such as glycerin, 4) with disintegrating agents, such as agar-agar, calcium carbonate , potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, f) with dissolution retarding agents such as paraffin, B with absorption accelerators such as quaternary ammonium compounds, 9) with wetting agents such as cetyl alcohol and glycerol monostearate, M) with absorbents such as kaolin and bentonite clay, and 1) with lubricants such as talc, calcium stearate, magnesium stearate , solid polyethylene glycols, sodium lauryl sulfate and their mixtures. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.

I00162| Solid compositions of this type can also be used as fillers in soft and hard filled gelatin capsules using fillers such as lactose or milk sugar, as well as high molecular weight polyethylene glycols, etc. Solid dosage forms of tablets, dragees, capsules, pills and granules can be formulated with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may be formulated to release the active ingredient(s) exclusively or preferentially in a specific section of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of this type can also be used as fillers in soft and hard filled gelatin capsules using fillers such as lactose or milk sugar, as well as high molecular weight polyethylene glycols, etc. 00163) The active compounds can also be present in microencapsulated form with one

With or more fillers as above. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be formulated with coatings and shells, such as enteric coatings, release control coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also contain, as in common practice, additional substances other than inert diluents, for example, lubricants for forming tablets and other auxiliary substances for forming tablets, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, dosage forms may also contain buffering agents. They may, optionally, contain agents that reduce transparency and may also have such a composition that they release the active ingredient(s) exclusively or preferentially in a defined section of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. (00164) Dosage forms for topical or transdermal administration of the compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers that may be required. ophthalmic composition, ear drops and eye drops are also considered to be included in the scope of this invention. In addition, the invention relates to the use of transdermal patches, which provide the additional advantage of ensuring controlled delivery of the compound into the body. Such dosage forms are obtained by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of a compound through the skin. The rate can be controlled either by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

І00165| As generally described above, the compounds of the invention can be used as inhibitors of voltage-gated sodium channels. In one embodiment, the compounds and compositions of the invention are Mau1.8 inhibitors, thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or reducing the severity of a disease, condition or disorder where activation or hyperactivity 60 Mam1.8 involved in a disease, condition or disorder. When activation or hyperactivity of Mah1.8 is involved in a particular disease, condition or disorder, the disease, condition or disorder may also be referred to as a "Mau1.8-mediated disease, condition or disorder".

Accordingly, in another aspect, the invention relates to a method of treating or alleviating the severity of a disease, condition, or disorder where activation or hyperactivity of Mau1.8 is involved in the disease state. (00166) The activity of a compound used in the present invention as a Mam1.8 inhibitor can be assayed by the methods described generally in the examples herein, or by methods available to one of ordinary skill in the art.

Additional therapeutic agents

I00167| It should also be understood that the compounds and pharmaceutically acceptable compositions of the invention can be used in methods of combination therapy, that is, the compounds and pharmaceutically acceptable compositions can be administered during, before or after the use of one or more other desired therapeutic agents or medical procedures. In one embodiment, the subject is treated with one or more additional therapeutic agents administered during, before, or after treatment with a compound or pharmaceutical composition of Formula I of the present invention. For the use of a specific combination of types of therapy (therapeutic agents or procedures) in a combined treatment regimen, it is necessary to take into account the compatibility of the desired therapeutic agents and/or procedures and the desired therapeutic effect. It should also be understood that the therapies used may have the desired effect on the same disorder (eg, a compound of the invention may be administered concurrently with another agent used to treat the same disorder) or may have different effects (eg, control which any adverse effects). As used herein, additional therapeutic agents typically administered to treat or prevent a particular disease or condition are known as "appropriate for a treatable disease or condition." For example, illustrative additional therapeutic agents include, but are not limited to: non-opioid analgesics (indoles such as etodolac, indomethacin, sulindac, tolmetin; naphthylalkanones such as nabumetone; oxicams such as piroxicam; para-aminophenol derivatives such as acetaminophen; propionic acids such as such as fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen,

From naproxen sodium, oxaprozin; salicylates, such as aspirin, magnesium choline trisalicylate, diflunisal; fenamates such as meclofenamic acid, mefenamic acid; and pyrazoles such as phenylbutazone) or opioid (narcotic) agonists (such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine). In addition, it is possible to use non-pharmacological methods of analgesia in combination with the introduction of one or more compounds according to the invention. For example, anesthesiological (intraspinal infusion, nerve blockade), neurosurgical (neurolysis of pathways in the central nervous system), neurostimulating (transcutaneous electrical stimulation of nerves, stimulation of the posterior column of the spinal cord), physiotherapeutic (physiotherapy, orthopedic devices, diathermy) or psychological (cognitive methods - hypnosis, biological feedback or behavioral methods) methods can also be used. Additional suitable therapeutic agents or methods are described generally in Te MegskK Mapiai, Mipesepii Eaiiop, Ea.

Vobep 5. Ropeg apa diviyp I... Kariap, Megoek Zpagr "bopte Sogr., a zirvziaiagu oi Megsk 5 So., Ips., 2011, and on the website of the Office for Quality Control of Food Products and Medicines, m/mliu . Eda.dom, the full contents of which are hereby incorporated by reference. 00168) In another embodiment, the additional therapeutic agent is an inhibitor

Mam1.7. Both ion channels Maum1.7 and Mau1.8 are highly expressed in sensory neurons of the dorsal root ganglia, where pain signals arise, but the different functional behavior of the two channels leads to their playing different and complementary roles in neuronal excitability. Mach1.7 controls the general sensitivity of nociceptive neurons and initiates the pain signal in the nociceptor. Maum1.8 amplifies and maintains the pain signal after its initiation. Because of these different roles, inhibition of both channels should increase the efficacy of pain relief.

Preclinical genetic knockout studies in mice support this idea, as double knockouts of Mau1.7 and Mau1.8 channels in EYE sensory neurons unexpectedly reduce nociceptive behavior to a greater extent than knockout of either channel alone.

I00169| In another embodiment, additional suitable therapeutic agents are selected from the following: 00170) (1) an opioid analgesic such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, levalorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene , nalmefene, nalorphine, naloxone, 60 naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;

00171) (2) nonsteroidal anti-inflammatory drug (NSAID), such as aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflubiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, or zomepirac; 00172) (3) a barbiturate sedative such as amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metabarbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal or thiopental; 00173) (4) a benzodiazepine that has a sedative effect, such as chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam; 00174) (5) a histamine antagonist (NI) that has a sedative effect, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine, or chlorcyclizine;

I00175| (6) a sedative such as glutethimide, meprobamate, methaqualone, or dichloralphenazone;

I00176| (7) a skeletal muscle relaxant such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or orphenadrine;

I00177| (8) MMOA receptor antagonist, for example dextromethorphan ((w)-3-hydroxy-M-methylmorphinan) or its metabolite dextrorphan ((w)-3-hydroxy-M-methylmorphinan), ketamine, memantine, pyrroloquinolinequinine, cis-4- -phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EM-3231 (MogrNirekhFf), the combined composition of morphine and dextromethorphan, topiramate, neramexan or perzinfotel, including the MK2B antagonist, for example irenprodil, traxoprodil or /(-)-(8)-6- 12-14-(3-fluorophenyl)-4-hydroxy-1-piperidinyl|-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone; 00178) (9) an alpha-adrenergic agent such as doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil or 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinoline- 2-yl)-5-(2-pyridyl)quinazoline;

I00179| (10) a tricyclic antidepressant such as desipramine, imipramine, amitriptyline, or nortriptyline;

From I00180| (11) an anticonvulsant such as carbamazepine (TedgeioIF), lamotrigine, topiramate, lacosamide (MitrayFv)), or valproate; 00181) (12) tachykinin (MC) antagonist, especially MK-3, MK-2 or MK-1 antagonist, for example (alphak,9k)-7-IZ,5-bis(trifluoromethyl)benzyl-8,9,10, 11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-P1,4|diazocinoi2,1-91(1,7|-naphthyridine-6-13-dione (TAK-637), 5-(2А ,35)-2-Ц1 8)-1-

3,5-bis(trifluoromethyl)phenyl|ethoxy-3-(4-fluorophenyl)-4-morpholinyl|methyl|-1,2-dihydro-ZH-1,2,4-triazol-3-one (MK-869 ), aprepitant, lanepitant, dapitant or 3-(2-methoxy-5-(trifluoromethoxy)phenyl|methylamino|-2-phenylpiperidine (25,35); (00182) (13) muscarinic antagonist, for example oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

I00183| (14) a selective COX-2 inhibitor, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib; (00184) (15) analgesics obtained from coal tar, in particular paracetamol; (00185) (16) antipsychotics such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepin, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindor, eplivanserin, osanetant, rimonabant, meclinertant, MigahiOpF, or sarizotan;

I00186| (17) an agonist (eg, resinferatoxin or civamide) or an antagonist (eg, capsazepine, ZKS-15300) of the vanilloid receptor;

I00187| (18) a beta-adrenergic agent such as propranolol; (00188) (19) a local anesthetic such as mexiletine; 00189) (20) a corticosteroid such as dexamethasone; 00190) (21) 5-HT receptor agonist or antagonist, in particular 5-HT1B/0O agonist, such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan; (00191) (22) 5-HTga receptor antagonist, such as K(h)-alpha-(2,3-dimethoxyphenyl)-I-(2-(4-fluorophenylethyl)|-4-piperidinemethanol (MY -100907); (00192) (23) cholinergic (nicotinic) analgesic, such as ispronicline (TS-1734), (E)-M-methyl-4-(3-pyridinyl)-3Z-buten-I-amine (KOUK-2403), (B)-5-(2-azetidinylmethoxy)-2-chloropyridine (АВТ-594) or nicotine; for (00193) (24) tramadol, tramadol EC (Shigat ECF)), tapentadol EC (Mysupiaf);

(00194) (25) a POE5 inhibitor such as 5-(2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl|- 1-methyl-3-n-propyl-1,6-dihydro-7H- pyrazolo|4,3-4|pyrimidin-7-one (sildenafil), (6К,12а)- 2,3,6,7,12,12а-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl) pyrazino|2",1":6,1 |pyridoyi3,4-

Biindole-1,4-dione (IS-351 or tadalafil), 2-(2-ethoxy-5-(4-ethylpiperazin-1-yl-1-sulfonyl)phenyl|-

B-methyl-7-propyl-ZN-imidazo|5,1-4(1,2,4Ytriazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl -2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazoloi|4,3-4|pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo|4,3- d9|Ipyrimidin-7-one, 5-(2-ethoxy-5-(4 -ethylpiperazin-1-ylsulfonyl)pyridin-3-yl|-3-ethyl-2-(2-methoxyethyl)-2,b-dihydro-7H-pyrazoloi|4,3-4|pyrimidin-7-one, 4- (3-chloro-4-methoxybenzyl)amino1|-2-

MK25)-2-(hydroxymethyl)pyrrolidin-1-yl|-M-(pyrimidin-2-ylmethyl)pyrimidin-5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-b, 7-dihydro -1 H-pyrazolo|4,3-4|pyrimidin-5-yl)-M-(2-(1-methylpyrrolidin-2-yl)ethyl|-4-propoxybenzenesulfonamide; 00195) (26) alpha-2-delta ligand, such as gabapentin (MeigopiapF), gabapentin SK (Sgaizeft), gabapentin enacarbil, (Nogilapif), pregabalin (IHugisa?F), 3-methylgabapentin, (alpha) 3(alpha|,5(alpha)(3-aminomethylbicyclo- I|3.2.0|hept-3-yl)-acetic acid, (35,5K)-3-aminomethyl-5-methylheptanoic acid, (35,5K)-3-amino-5--methylheptanoic acid, (35, 5K)-3-amino-5-methyloctanoic acid, (25,45)-4-(3-chlorophenoxy)proline, (25,45)-4-(3-fluorobenzyl)proline, ((1E,5K,65) -6-(aminomethyl)bicyclo|3.2.0|hept-b-yl|acetic acid, 3-(1-aminomethylcyclohexylmethyl)-4H-/1,2,4|oxadiazol-5-one, C-(11-( 1H-tetrazol-5-ylmethyl)cycloheptyl|methylamine, (35,45)-(1-aminomethyl-3,4-dimethylcyclopentyl)-acetic acid, (35,5K)-3-aminomethyl-5--methyloctanoic acid, ( 35.5K)-3-amino-x-methyln onanoic acid, (35,5K)-3-amino-5-methyloctanoic acid, (ZK,4K,5K)-3-amino-4,5-dimethylheptanoic acid and (ZK,4K,5K)-3-amino-4 ,5-dimethyloctanoic acid; 00196) (27) a cannabinoid such as KNK-6188; (00197) (28) antagonist of metabotropic glutamate receptors subtype 1 (tShyA)|); (00198) (29) a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, 4,I-fenfluramine, femoxetine, ifoxetine, cyanodothiepine, litoxetine, dapoxetine, nefazodone, cericlamine, and trazodone; 00199) (30) norepinephrine (norepinephrine) reuptake inhibitor such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion, nomiphensine and viloxazine (Mimaiapf)), especially selective norepinephrine reuptake inhibitor, such as reboxetine, in particular (5,5)-reboxetine; 00200) (31) a dual serotonin-norepinephrine reuptake inhibitor such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clopyramine, clopyramine metabolite desmethylclopyramine, duloxetine (SutbagGayeF)), milnacipran, and imipramine;

И0О2О1| (32) an inhibitor of inducible nitric oxide synthase (NOS), such as 5-(2-K1-iminoethyl)amino|ethyl|)-I -homocysteine, 5-(2-(1-iminoethyl)amino|ethyl|)-4 ,4-dioxo-I -cysteine, 5-(2-K1-iminoethyl)amino|ethyl|-2-methyl-1-cysteine, (25,52)-2-amino-2-methyl-7-|(( 1-iminoethyl)amino|-5-heptenoic acid, 2-ISHK18,35)-3-amino-4-hydroxy-1-(5-thiazolyl)butylthio|-5-chloro-5-pyridinecarbonitrile; 2-1 A,35)-3-amino-4-hydroxy-1-(5-thiazolyl)butylthio|-4-chlorobenzonitrile, (25,48)-2-amino-4-C(2g-chloro-5- (trifluoromethyl)phenylhyo|-5-thiazolbutanol, 2-I(SHK18,35)-3-amino-4-hydroxy-1-(5-thiazolyl)butylhyo|-6-"(trifluoromethyl)-3-pyridinecarbonitrile, 2- C1,35)-3-amino-4-hydroxy-1-(5-thiazolyl)butylthio|-o-chlorobenzonitrile, IM-(4-(2-(3- chlorobenzylamino)ethylIphenylthiophene-2-carboxamidine, МХМ-462 or guanidinoethyl disulfide; (002021 (33) an acetylcholinesterase inhibitor such as donepezil; (00203) (34) a prostaglandin E2 subtype 4 (ER4) antagonist such as M-|(((2-(4-(2-ethyl-4,6 - dimethyl-1H-imidazo(|4,5-c|Ipyridine-I-i l/uphenyl|ethyl)amino)-carbonyl|-4-methylbenzenesulfonamide or 4-K15)-I-C(5-chloro-2- (3-fluorophenoxy)pyridin-3-ylcarbonyl)iamino)ethyl|benzoic acid; (00204) (35) a leukotriene B4 antagonist such as 1-(3-biphenyl-4-ylmethyl-4-hydroxychroman-7-yl-cyclopentanecarbonate) acid (СР-105696), 5-(2-(2-carboxyethyl)-3-(6-(4-methoxyphenyl)-

BE-hexenyloxyphenoxy|valeric acid (0МО-4057) or ОРС-11870; (002051 (36) 5-lipoxygenase inhibitor such as zileuton, 6-|((3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxymethyl| -1-methyl-2-quinolone (20-2138) or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (SM-6504); (00206) (37) sodium blocker channels, such as lidocaine, lidocaine cream plus tetracaine (785-201), or eslicarbazepine acetate;

I00207| (38) Maum1.7 blocker, such as XEM-402 and such as described in UMO 2011/140425; UMO 2012/106499; MO 2012/112743; MO 2012/125613; UMO 2013067248 or PCT/О52013/21535, the full content of each application is hereby incorporated by reference. 00208) (39) blocker Mauhm1.8, such as described in UMO 2008/135826 and UMO 2006/011050, the full content of each application is hereby incorporated by reference. 00209) (40) a combined blocker of Mam1.7 and Mam1.8, such as OBR-2230 or VI-1021; 00210) (41) a 5-NTZ antagonist such as ondansetron; (00211) (42) TREM 1 receptor agonist, such as capsaicin (Meigodeb5xF?, Oshepaf); and its pharmaceutically acceptable salts and solvates; (00212) (43) a nicotinic receptor antagonist such as varenicline; (00213) (44) an M-type calcium channel antagonist such as 2-160; (00214) (45) a nerve growth factor antagonist such as tanezumab; (00215) (46) an endopeptidase stimulator, such as senrebotase; (00216) (47) an angiotensin II antagonist such as EMA-401.

I00217| In one embodiment, additional suitable therapeutic agents are selected from M-116517, pregabalin, controlled-release pregabalin, ezogabine (Royidaf), topical ketamine/amitriptyline cream (Atiqueke), AMP-923, perampanel (E-2007), ralfinamide, transdermal bupivacaine (EiIadig8), SMM1014802, 9MO-10234094 (carisbamate), BM5-954561 or AKS-4558. 00218) The amount of additional therapeutic agent present in the compositions according to the present invention can be no more than the amount that is usually introduced into the composition containing this therapeutic agent as the only active agent. The amount of additional therapeutic agent in the currently described compositions can range from about 1095 to 10095 of the amount normally present in a composition containing this agent as the only active agent.

I00219| The compounds of the present invention or their pharmaceutically acceptable compositions can also be included in compositions for coating implanted medical devices such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the invention, in another aspect, relates to a composition for coating an implantable device comprising a compound of the invention as generally described above and in the classes and subclasses herein, and a carrier suitable for coating said implantable device. In another aspect, the invention relates to an implantable device coated with a composition comprising a compound of the invention as generally described above and in the classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and general preparation of coated implantable devices are described in US Pat. No. 6,099,562; 5886026 and 5304121.

Coatings, as a rule, are biocompatible polymer materials, such as hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate and their mixtures. The coating may optionally be additionally coated with a suitable surface coating of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to provide controlled release characteristics of the composition.

I00220| Another aspect of the invention relates to the inhibition of Mam1.8 activity in a biological sample or subject, where the method includes administering to the subject a compound of formula I or a composition containing said compound, or bringing said biological sample into contact with them.

The term "biological sample" as used herein includes, but is not limited to, cell cultures or extracts thereof; material obtained during a biopsy from a mammal or its extracts; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof. 00221) Inhibition of Mach1!.8 activity in a biological sample can be used for a variety of purposes known to one skilled in the art. Such purposes include, but are not limited to, the study of sodium channels in biological and pathological phenomena and the comparative evaluation of novel sodium channel inhibitors.

SCHEMES AND EXAMPLES

I00222| The following definitions describe the terms and abbreviations used in this document.

Ac acetyl

You are butyl

KE ethyl

PH phenyl

Me methyl 5O0

TNE tetrahydrofuran rum dichloromethane

SNS: g dichloromethane

EOAc ethyl acetate

СсниСМ acetonitrile mesm acetonitrile

AFM acetonitrile

EUN ethanol

EBO simple diethyl ether meon methanol

II-RGOH isopropyl alcohol

MTBE methyl-tert-butyl simple ether

OME M,M-dimethylformamide

OMA M,M-dimethylacetamide pM5o dimethylsulfoxide

NOAc is acetic acid

MM M-methylpyrrolidinone

TEA triethylamine

TEA trifluoroacetic acid

TEAA trifluoroacetic anhydride

EVM or MEI with triethylamine

SULFUR: or SOIBEA / diisopropylethylamine

K»COz potassium carbonate

MagSOz sodium carbonate

Mag52Oz sodium thiosulfate

C8v2bO»z cesium carbonate

Mmansoz sodium bicarbonate maon sodium hydroxide

Ma»5O4 sodium sulfate

Mazoch, magnesium sulfate

KzROH potassium phosphate

MNAaSI ammonium chloride

ZO202 thionyl chloride

KMpo potassium permanganate

LOBSTER M,M-dimethylaminopyridine hexafluorophosphate 1-

NATO Ibis(dimethylamino)methylene|-1H-1,2,3-triazol4,5-b|pyridinium-3-oxide

EOSI hydrochloride M-(3-dimethylaminopropyl)-M'-ethylcarbodiimide

NEW hydrate of 1-hydroxybenzotriazole

NOI hydrochloric acid and water ra/s palladium on carbon

MaOdAs sodium acetate

Hg5OH sulfuric acid

Me nitrogen gas

Ng gaseous hydrogen p-Vigy n-butyllithium

PaA(OAcS)2 palladium acetate)

РНз triphenylphosphine

Mvo M-bromosuccinimide

Tetrakis(triphenylphosphine)palladium(O)

I C/M5 liquid chromatography/mass spectrometry asM5 gas chromatography-mass spectrometry

HPLC, high-performance liquid chromatography, and gas chromatography

IS liquid chromatography

IC ion chromatography hour or hour. hours

MIN. minutes atm. atmospheres n or KT room temperature

NIC; thin layer chromatography

ZM starting substance equiv. or equiv. equivalents of water

H normal l liters ml milliliters μl microliters

M molar

MKM is micromolar

NM nanomolar mol mol mmol millimole

G gram

MG milligrams

ICG micrograms "H-NMR proton nuclear magnetic resonance

MHz megahertz

Hz Hertz

COSyz deuterochloroform pM5o-y6 deuterodimethylsulfoxide

Me deuteromethanol

Sozoo0 deuteromethanol

Ki is the dissociation constant

ISvo is half of the maximum inhibitory concentration

I00223| The compounds of the invention can be easily prepared using the following methods. Schemes 1-3 below illustrate general methods of preparing the compounds of the present invention.

Scheme 1. General preparation of compounds of the formula I on b b b i o In the action i Tse i vo

E: on v2 M v/m v2 M moe z --- Н ОО 0 -- Н оо

B , R (ev) VE (c) VZ o vo

Kk ri in «i in em! (c) in r" on the 2nd SI

VE ri (a) 3-Aminophenylsulfonamide, binder (i.e. NATI, EOSI, NOVT), base (i.e.

M-methylmorpholine), solvent (ie OME, dichloromethane); (b) 3-aminophenylsulfonamide, base (ie, pyridine, C52CO3), solvent (ie, dichloromethane, OME); (c) base (i.e. Mann, С52СО3,

MagSO»z, MansSoz), solvent (OME, MMP, dioxane), AT; (4) 5O02SiI», OME in a solvent (i.e., dichloromethane).

Scheme 2. General preparation of compounds of the formula I. D6) v7 v! Gee! in: v2 o

Н ОН в2 Но 3 Е : M skh y at OA vo "dv bo v 4 i: Kk Kv re vv ro v (B) v! v: CM v E ro (a) i) Base (i.e. Man, С52СОз, Mag6СОз . ) i) base (i.e. Man, C52CO3, MagCO3, Mansoz), solvent (OME, MMP, dioxane), LT; iii) hydrolysis conditions (i.e. aqueous HBr); (c) 3-aminophenylsulfonamide, binding agent (i.e. NATI , EOSI, NOVT), base (i.e. M-methylmorpholine), solvent (i.e. OME, dichloromethane).

Scheme 3. General preparation of compounds of formula I and KH o

Vg ULN» a: M /in Kz LNe

Vite N bo - 3525 im 5 - v.-- N yo o (a) 1 | K-E (F) (6) ro ro (F) vo vo vo voi v" vo ro ro 7 i; (a) A8Z-B(OH)2 (i.e. Mev(OH)"), catalyst Ra (i.e. (PPH3) "Ra"), solvent (i.e. dimethoxyethane), base (i.e. MagCO3).

I00224| Scheme C above can be used to insert a plurality of K"', B, BZ and KU groups starting with an aryl bromide. The scheme above shows the presence of, for example, an EC group and an aryl bromide reacting with a suitable boronic acid under Suzuki-type conditions for substitution bromide group to the KZ group.One skilled in the art will appreciate that multiple B'-8- groups can be inserted starting with the aryl bromide using this method.

EXAMPLES

I00225| General methods. H-NMR spectra (400 MHz) were obtained as solutions in a suitable deuterated solvent, such as dimethylsulfoxide-2 (0OM5O). Mass spectra (M5) were obtained using an ARRIEY Viosubiet5 ARI EX I C/M5 system. Purity and retention time compounds were determined by reversed-phase HPLC using a Kipei C18 column (50x2.1 mm, 1.7 μm particles) from Rpepotepeh (rp: 008-4475-AM) and double passage of a 1-9995 gradient of mobile phase B for 3 minutes. 25. A-H2O (00595 СезСбО»2Н). Mobile phase B-СНзиСМ (0.0595 СезСО»2Н). The flow rate is 2 ml/min., the injection volume is 3 μl, and the column temperature is 50 "С . Gel chromatography on silica gel was performed using silica gel-b60 with a particle size of 230-400 mesh. Pyridine, dichloromethane, tetrahydrofuran, dimethylformamide, acetonitrile, methanol, 1,4-dioxane, and other commonly used solvents were prepared, for example, from VaKeg or AlgisN, and in some cases the reagents were in hermetically sealed bottles of AlIdgisN stored under dry nitrogen . All reaction mixtures were stirred on a magnetic stirrer unless otherwise noted.

EXAMPLE 1

Preparation of 2-fluoro-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide

Io

E E MN vo si in MN and MV

Nom r: N oo v E oo E (00226) To a solution of 3-aminobenzenesulfonamide (18.77 g, 109.0 mmol) and pyridine (88.16 ml, 1.090 mol) in dichloromethane (247.0 ml) at 0" 2-Fluoro-5-(trifluoromethyl)benzoyl chloride (24.7 g, 109.0 mmol) was added dropwise to C. The mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was diluted with dichloromethane and water. The layers were separated and the organic the layer was washed with aqueous 1N HCl (2x). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The precipitate was triturated with dichloromethane and filtered. The white solid was washed with diethyl ether and collected by vacuum filtration to give 2-fluoro-M -(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide (23.83 g, 6095) as a white solid.

Mass/charge according to E5BI-M5: calculated 362.03, found 363.3 (M.-1)-. Dwell time: 1.37 minutes (skip from 1 minute). "H-NMR (400 MHz, OM50-av) b 10.91 (s, 1H), 8.30 (s, 1H), 8.15-8.07 (m, 1H), 8.06-7, 97 (m, 1H), 7.89-7.83 (m, 1H), 7.64 (t, U-9.2 Hz, 1H), 7.62-7.54 (m, 2H), 7 ,42 (c, 2H) m.h.

EXAMPLE 2

Preparation of 2-fluoro-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide (8)

So s eyya

Si i u chno

M Z bo EZS E

I00227| Pyridine (10.7 ml, 132.4 mmol), and the mixture was stirred at room temperature for 15 hours.

Water (50 mL) was added to the reaction mixture and the product precipitated rapidly. The solid was isolated by filtration, washed with water (2x75 ml) and dried in vacuo to give 2-fluoro-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide (4.43 g) as a cream solid. The solvent was evaporated under reduced pressure. Water was added and the mixture was set aside.

After a few minutes, a solid precipitated. The solid was isolated by filtration,

Zo was washed with water (2x30 ml) and dried in a vacuum to obtain a second portion of the desired product (2.7 g). The two portions were combined to give 2-fluoro-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)-benzamide (7.13 g, 8895) as a solid. Mass/charge by E5I-M5: calculated 362.03, found 363.3 (M--1)". Retention time: 1.63 minutes (3 minute pass). "H-NMR (400 MHz, OM50O-av) b 10.93 (c, 1H), 8.35-8.27 (m, 1H), 7.99-7.88 (m, 2H), 7.88-7.80 (m, 1H), 7 .76 (d, 9U-8.0 Gu, 1H), 7.65-7.51 (m, 2H), 7.43 (s, 2H) m.h.

EXAMPLE Z

Preparation of 4-chloro-2-fluoro-M-(3-sulfamoylphenyl)benzamide

Eat and soy in "MN u/va Nam o? so oo s E oo si E

I00228| Pyridine (939.0 μL, 11.61 mmol) was added slowly to a solution of 4-chloro-2-fluorobenzoyl chloride (1.1 g, 5.81 mmol) and 3-aminobenzenesulfonamide (1 g, 5.81 mmol) in dichloromethane ( 5 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and the precipitate was washed with dichloromethane and water to give 4-chloro-2-fluoro-N-(3-sulfamoylphenyl)benzamide (1.8 g, 92.295) as a white solid. Mass/charge according to E5BI-M5: calculated 328.01, found 329.1 (Ma-1)7. Dwell time: 1.47 minutes (skip from 1 minute). "H-NMR (400 MHz, OM50-av) b 10.78 (s, 1H), 8.31 (s, 1H), 7.84 (d, U-6.8 Hz, 1H), 7.74 (t, U-8.0 Hu, 1H), 7.66 (dd, 9U-10.0, 1.9 Hu, 1H), 7.57 (m, 2H), 7.46 (dd, U- 8.3, 1.9 Hz, 1H), 7.41 (s, 2H) m.h.

EXAMPLE 4

Preparation of 5-chloro-2-fluoro-M-(3-sulfamoylphenyl)benzamide i i, si ui si MH»

E oo E

I00229| A mixture of 5-chloro-2-fluorobenzoic acid (349.1 mg, 2.0 mmol), 3-aminobenzenesulfonamide (413.3 mg, 2.4 mmol), NATO (608.4 mg, 1. mmol) and M- of methylmorpholine (439.8 μl, 4.0 mmol) in OME (4 ml) was stirred at 40 °C for 1 h. The reaction mixture was poured into water, the pH was adjusted to 4, and the mixture was extracted with ethyl acetate (3x). combined, washed with water, saturated saline solution, dried over Mag50O54, filtered and evaporated to dryness to obtain 5-chloro-2-fluoro-M-(3-sulfamoylphenyl)benzamide (0.36 g, 5595) as a pale yellow solid .

Mass/charge on E5I-M5: calculated 328.01, detected 329.1 (M--1)". Retention time: 1.41 minutes (passing 3 minutes).

EXAMPLE 5

Preparation of 2-fluoro-4-methyl-N-(3-sulfamoylphenyl)benzamide about cx 6)

SC "MN"; uva: well, it's a beast

E oo E

I00230| Pyridine (1.0 mL, 12.98 mmol) was added dropwise to a mixture of 2-fluoro-4-methylbenzoyl chloride (2.24 g, 12.98 mmol), 3-aminobenzenesulfonamide (2.235 g, 12.98 mmol), and dichloromethane. (40.32 mL) at room temperature. The mixture was stirred at room temperature for 2.5 hours before adding water (150 ml). The mixture was filtered and the solid was collected by vacuum filtration. The solid was suspended in diethyl ether (30 mL) and filtered (twice). The solid was placed in a vacuum oven at 40 °C overnight to give 2-fluoro-4-methyl-N-(3-sulfamoylphenyl)benzamide (1.81 g, 4595) as an off-white solid. E5BI-M5: calculated 308.06, detected 309.5 (Mya-1)-. Retention time: 1.42 minutes (3 minute pass). "H-NMR (400 MHz, OM50-av) b 10.61 ( c, 1H), 8.32 (c, 1H), 7.89-7.80 (m, 1H), 7.62-7.51 (m, ЗН), 7.39 (c, 2H), 7 ,24-7.11 (m, 2H), 2.39 (s, ZN) m.h.

EXAMPLE 6

Preparation of 4-cyano-2-fluoro-M-(3-sulfamoylphenyl)benzamide i. what

MN"

M

Mo E oo Mo E

From II00231| A solution of 4-cyano-2-fluorobenzoic acid (495.4 mg, 3.0 mmol), 3-aminobenzenesulfonamide (516.6 mg, 3.0 mmol), EOSI (575.1 mg, 3.0 mmol), NOVT (405.4 mg, 3.0 mmol) and M-methylmorpholine (659.7 μl, 6.0 mmol) in OME (4 ml) were stirred at 25" for 16 hours. The reaction mixture was poured into 1N HCl and extracted with ethyl acetate ( 3x).

The organic substances were combined and washed with TTN HCl (3x), water, saturated saline solution, dried over Ma»5Oi, filtered through a short plug of silica gel and evaporated to dryness to give 4-cyano-2-fluoro-N-(3-sulfamoylphenyl) )benzamide (860 mg, 9095) as a white solid, which was used in subsequent stages without further purification. Mass/charge according to E5I-M5: calculated 319.04, found 320.1 (M'1)".

Dwell time: 1.04 minutes (skip from 1 minute).

EXAMPLE 7

Preparation of 5-cyano-2-fluoro-M-(3-sulfamoylphenyl)benzamide and Its.

Mo and uv Mo "Me

E oo E

I00232| A solution of 5-cyano-2-fluorobenzoic acid (165.1 mg, 1.0 mmol), 3-aminobenzenesulfonamide (206.6 mg, 1.20 mmol), NATO (342.2 mg, 0.90 mmol) and M - methylmorpholine (219.9 μl, 2.0 mmol) in OME (2 ml) was stirred at 25 "C for 4 hours.

The reaction mixture was poured into water and extracted with ethyl acetate (3). The organic substances were combined, washed with water, acidified to ri-4 with 1H HCl and extracted with ethyl acetate (3x). The organic substances were combined, washed with water, saturated saline solution, dried with the help of Mag5O", filtered and evaporated to dryness to obtain

B-cyano-2-fluoro-M-(3-sulfamoylphenyl)benzamide (150 mg, 4795), which was used in subsequent stages without further purification. Mass/charge according to E5I-M5: calculated 319.04, found 320.1 (M'n1)7. Dwell time: 0.97 minutes (skip from 1 minute).

EXAMPLE 8

Preparation of 2,4-difluoro-M-(3-sulfamoylphenyl)benzamide and Y1.

MN

So in M?

E E oo E E

I00233| To a mixture of 2,4-difluorobenzoyl chloride (2.0 g, 11.33 mmol), 3-aminobenzenesulfonamide (1.95 g, 11.33 mmol), and dichloromethane (36.0 mL) was added pyridine (3.7 mL, 45 .32 mmol) at 25 "C. The mixture was stirred at 25 "C for 18 hours before it was washed with T1N HCl and water. The organic layer was dried over sodium sulfate, filtered and concentrated. The precipitate was subjected to column chromatography (0-10095 ethyl acetate/hexanes) to give 2,4-difluoro-N-(3-sulfamoylphenyl)benzamide (2.0 g, 57905).

Mass/charge according to E5BI-M5: calculated 312.04, found 313.1 (M.-1)-. Dwell time: 1.31 minutes (skip from 1 minute). "H-NMR (400 MHz, OM50O-av) 6 10.73 (s, 1H), 8.91 (s, 1H), 7.89-1.714 (m, 2H), 7.62-7.52 ( m, 2H), 7.51-7.42 (m, 1H), 7.41 (s, 2H), 7.26 (td, 9U-8.4, 2.2 Gu, 1H) m.h.

EXAMPLE 9

Preparation of 2,5-difluoro-M-(3-sulfamoylphenyl)benzamide ko,

E in E "Mn;

E oo E (00234) To a solution of 3-aminobenzenesulfonamide (1.0 g, 5.81 mmol) and pyridine (4.7 ml, 58.07 mmol) in dichloromethane (10.3 ml) at 0 "С was added dropwise 2,5-difluorobenzoyl chloride (719.3 µL, 5.81 mmol).The mixture was allowed to warm to 25 °C and stirred for 72 hours.

The reaction mixture was diluted with ethyl acetate and water. The layers were separated, and the organic layer

Zo was washed with a saturated saline solution (2x). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a clear oil which crystallized on standing. The solid was redissolved in ethyl acetate and washed with 1N HCl (3x). The organic layer was dried with MaozoO»4, filtered and evaporated to give 2,5-difluoro-M-(3-sulfamoylphenyl)benzamide (1.17 g, 6495) as a white solid. Mass/charge according to E5BI-M5: calculated 312.04, found 313.3 (M.1)7.

Dwell time: 1.31 minutes (skip from 1 minute). "H-NMR (400 MHz, OM50O-av) b 10.81 (s, 1H), 8.31 (s, 1H), 7.84 (d, 929.1 Hu, 1H), 7.59-7 .54 (m, ZN), 7.50-7.39 (m, 4H) m.h.

EXAMPLE 10

Preparation of 2,5-difluoro-4-methyl-M-(3-sulfamoylphenyl)benzamide

For

E ER "MN"

E oo E

I00235| A solution of 3-aminobenzenesulfonamide (413.3 mg, 2.40 mmol), 2,5-difluoro-4-methylbenzoic acid (344.3 mg, 2.0 mmol), NATIi (684.4 mg, 1.80 mmol) and M-methylmorpholine (439.8 μl, 4.0 mmol) in OME (2 ml) were stirred at 40 "C for 2 hours. The reaction mixture was poured into TTN HCl and extracted with ethyl acetate (3x). The organic substances were combined, washed water saturated with saline, dried with Mag5O»4 and evaporated to dryness to give 2,5-difluoro-4-methyl-N-(3-sulfamoylphenyl)benzamide (610 mg, 9495) as a solid, which was used in the next stage without additional purification.E5I-Me mass/charge: calculated 326.05, found 327.3 (Ma1)-.Retention time: 1.25 minutes (3 minute skip).

EXAMPLE 11

Preparation of 2-fluoro-M-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide

SEZ O SEZ O u/ fe chn

E oo E (00236) To a solution of 3-aminobenzenesulfonamide (760.1 mg, 4.41 mmol) in dichloromethane (10 ml) was added 2-fluoro-6-"(trifluoromethyl)benzoyl chloride (1 G, 4.41 mmol), 3-aminobenzenesulfonamide (760.1 mg, 4.41 mmol) and pyridine (1.1 mL, 13.24 mmol), and the mixture was stirred at 25 "C for 12 hours. The reaction mixture was diluted with dichloromethane and water. The 2 layers were separated, and the organic layer was washed with water and 1H N.C. The organics were combined and evaporated to give 2-fluoro-M-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide (600 mg, 3795) as a pale pink solid. Mass/charge by E5BI-M5: calculated 362.03, detected 363.3 (Mya-1):. Retention time: 1.39 minutes (transmission of 3 minutes). "H-NMR (400 MHz, SOzZSM) b 9, 18 (s, 1H), 8.31 (t, 9-1.9 Hz, 1H), 7.83-7.AZ (m, 6H), 5.75 (s, 2H) m.ch.

EXAMPLE 12

Preparation of 5-(difluoromethyl)-2-fluorobenzoic acid 6)

IS

I00237| 2-Fluoro-5-methylbenzoic acid (2 g, 12.98 mmol), MW5 (6.0 g, 33.75 mmol) and benzoyl peroxide (157.2 mg, 0.65 mmol) in SiCl (30 mL) were heated under reflux for 48 hours. The solids were filtered off and washed with dichloromethane. The solvent was evaporated and the precipitate was taken up in ethanol (30 mL) and heated to 50 °C. A solution of silver nitrate (2.20 g, 12.98 mmol) in 5 mL of water was added dropwise. The mixture was stirred for 45 min, cooled to 25 °C , then poured into 1H NS. The solids were filtered off and washed with EN. EN was removed, and the aqueous layer was extracted with ethyl acetate (3x). The organic substances were combined, washed with a saturated saline solution, dried over Mag2505 and evaporated to dryness. Purification by column chromatography using a gradient of ethyl acetate in hexanes (0-5095) gave 2-fluoro-5-

From formylbenzoic acid (0.33 g, 1595) as a light yellow solid. Mass/charge by

E5BI-M5: calculated 168.02, detected 169.1 (Ma1)-. Dwell time: 0.49 minutes (skip from 1 minute). "H-'NMR (400 MHz, OM5O-av) b 13.64 (s, 1H), 10.03 (s, 1H), 8.43 (dd, 9-7.2,2.2 Hz, 1H ), 8.17 (ddd, 9U-8.4, 4.7, 2.2 Hz, 1H), 7.56 (dd, 9U-10.6, 8.6 Hz, 1H) m.h. ( 00238) Deoxyfluorine (566.8 μl, 3.07 mmol) was added to methyl 2-fluoro-5-formylbenzoate (280 mg, 1.54 mmol) followed by 2 drops of ethanol, and the reaction mixture was stirred at 25°C for 4 hours More deoxyfluorine (100 μL, 0.54 mmol) was added, and the reaction mixture was stirred for an additional hour. The reaction in the mixture was carefully quenched with a saturated aqueous solution of sodium bicarbonate, and then extracted with ethyl acetate (3x). The organic substances were combined, washed with water, saturated saline, dried over NaCl, filtered and evaporated to dryness. Purification by column chromatography using a gradient of ethyl acetate in hexanes (0-2095) afforded methyl 5-(difluoromethyl)-2-fluorobenzoate (230 mg, 7395) as a clear oil.

Mass/charge by E5BI-M5: calculated 204.04, detected 204.9 (M.-1)". Retention time: 1.31 minutes (3 minute skip). "H-NMR (400 MHz, SOSI3) b 8.26-8.05 (m, 1H), 7.81-7.58 (m, 1H), 7.29-7.19 (m, 1H), 6.66 (t, 9U-56.1 Hz, 1H), 3.96 (s, ЗН) m.h. (00239) To a solution of methyl 5-(difluoromethyl)-2-fluorobenzoate (230 mg, 1.127 mmol) in TNE (4 ml) was added a solution of GION (269.9 mg, 11.27 mmol) in water (1 ml), and the reaction mixture was stirred at 25 "C for 4 hours. The pH of the reaction mixture was adjusted to 4 with 4N HCl, and then extracted with ethyl acetate (3x). The organic substances were combined, washed with water, saturated saline, dried over Mag250O54, filtered and evaporated to dryness to give

B-(difluoromethyl)-2-fluorobenzoic acid (187 mg, 8795) as a white solid.

Mass/charge according to E5I-M5: calculated 190.02, found 191.3 (Ma-1)-. Holding time: 1 minute (skip from 1 minute).

EXAMPLE 13

Preparation of 5-(difluoromethyl)-2-fluoro-M-(3-sulfamoylphenyl)benzamide and Its

Rene in ens MN" in I same vom So oho

E oo E

I00240| To a solution of 5-(difluoromethyl)-2-fluorobenzoic acid (95.1 mg, 0.50 mmol), 3-aminobenzenesulfonamide (94.7 mg, 0.55 mmol) and M-methylmorpholine (109.9 μl, 1, 0 mmol) in

OME (1 mL) was added NATI (209 mg, 0.55 mmol) and the reaction mixture was stirred at 257 for 1 hour. The reaction mixture was poured into 1N HCl and extracted with ethyl acetate (3x).

The organic substances were combined, washed with water (2x), saturated saline solution, dried with Mag5O:, filtered and evaporated to dryness. Purification by silica gel column chromatography using a 20-8095 gradient of ethyl acetate in hexanes gave 5-(difluoromethyl)-2-fluoro-N-(3-sulfamoylphenyl)benzamide (202 mg, »10095), which was used in the next step without additional cleaning.

Mass/charge according to E5BI-M5: calculated 344.04, found 345.3 (M.-1)-. Dwell time: 1.19 minutes (skip from 1 minute).

EXAMPLE 14

Preparation of 5-bromo-4-chloro-2-fluoro-M-(3-sulfamoylphenyl)benzamide and what

You are in the Russian Federation Vg No

M still on call -- 94 points

SI E oo SI E

I(00241| To 5-bromo-4-chloro-2-fluorobenzoic acid (5.0 g, 19.73 mmol), 3-aminobenzenesulfonamide (5.1 g, 29.60 mmol), 1-hydroxybenzotriazole (2, 93 g, 21.70 mmol), 3-(ethyliminomethylamino)-M,M-dimethylpropan-1-amine hydrochloride (4.2 g, 21.70 mmol) and M,M-dimethylformamide (80 ml) was added triethylamine (5 .5 mL, 39.46 mmol) and stirred at room temperature for 18 hours. The solvent was evaporated. The reaction mixture was washed with 1M hydrochloric acid solution (3x50 mL), saturated aqueous sodium bicarbonate solution (3x50 mL), and saturated aqueous sodium chloride solution (3x50 The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. The crude product was dissolved in dichloromethane, and the precipitate was isolated by filtration to give 5-bromo-4-chloro-2-fluoro-N-(3-sulfamoylphenyl)benzamide (4, 0 g, 35965) in the form of a gray solid

Zo was used in the next stage without additional purification. Mass/charge according to E5I-M5: calculated 405.92, found 407.0 (M-a-1)-. Holding time: 1.7 minutes (skip from 1 minute). "H-NMR (400 MHz, OM50O-av) b 10.84 (s, 1H), 8.32-8.24 (m, 1H), 8.13 (d, 9-7.0 Hz, 1H) , 7.90 (d, 9-9.7 Hz, 1H), 7.86-7.81 (m, 1H), 7.61-7.53 (m, 2H), 7.42 (s, 2H ) m.ch.

EXAMPLE 15

Preparation of 2-fluoro-M-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide and. "MN"e uva; Nm zvyNe -- uv oo

ЕЗСО Е оо ЕЗСО Е (002421) To 2-fluoro-4-(trifluoromethoxy)benzoic acid (5 g, 22.31 mmol) in thionyl chloride (2.43 ml, 33.46 mmol) was added M,M-dimethylformamide (491 .6 μl, 6.38 mmol). The reaction mixture was stirred at room temperature for 17 hours. Excess thionyl chloride and

M,M-dimethylformamide was removed in vacuo to give 2-fluoro-4-(trifluoromethoxy)benzoyl chloride, which was used in the next step without further purification. (00243) To 3-aminobenzenesulfonamide (4.79 g, 27.83 mmol) was added potassium carbonate (3.85 g, 27.82 mmol), methyl tert-butyl ether (27.0 mL), and water (27 .0 ml). The reaction mixture was cooled to 0 "C. 2-Fluoro-4-(trifluoromethoxy)benzoyl chloride (5.4 g, 22.26 mmol) in dichloromethane (13.5 mL) was added to the intensively stirred reaction mixture. The reaction mixture was stirred at room temperature for 30 hours. The reaction mixture was a suspension. The product was isolated by filtration using ether. The product was applied to celite and purified by chromatography on silica gel using a gradient of 0-50905 ethyl acetate in dichloromethane to give 3 g (3595) of 2-fluoro-M -(Z-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide." H-NMR (400 MHz, OM50-av) b 10.83 (s, 1H), 8.38-8.25 (m, 1H), 7 .90-7.18 (m, 2H), 7.66-7.52 (m, ZN), 7.47-7.36 (m, ZN) m.h. Mass/charge according to EBI-M5: calculated 378.03, found 379.4 (M--1)7. Dwell time: 1.56 minutes (skip from 1 minute).

EXAMPLE 16

Preparation of 2-fluoro-4-(perfluoroethyl)-M-(3-sulfamoylphenyl)benzamide in

MN schi Son

Soge E o Sov E (00244) Through a stirred solution of 4-bromo-2-fluorobenzoic acid (3.0 g, 13.70 mmol) and copper (8.70 g, 137.0 mmol) in OM5O (56.3 mL ) bubbled 1,1,1,2,2-pentafluoro-2-iodoethane (23.6 g, 95.90 mmol) in the bomb. The vessel was sealed and heated at 120 C for 72 hours.

The reaction mixture was diluted with water and filtered through a plug of silica gel and then extracted with ethyl acetate (4x). The organic substances were combined, washed with a saturated saline solution, dried (Mag25O04) and evaporated to dryness. Purification by column chromatography using a gradient of 0-4095 ethyl acetate in hexanes afforded 2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoic acid (1.81 g, 5195) as a white solid . Mass/charge according to E5I-M5: calculated 258.01, found 259.3 (Ma1)5. Holding time: 1.45 minutes. (00245) Solution of 2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)benzoic acid (516.2 mg, 2.0 mmol),

3-aminobenzenesulfonamide (378.9 mg, 2.20 mmol), NATO (836.5 mg, 2.20 mmol) and M-methylmorpholine (439.8 μL, 4.0 mmol) in OME (6 mL) were stirred at at room temperature for 16 hours. The reaction mixture was poured into water, the pH was adjusted to 4 with 1N NaCl, and extracted with ethyl acetate (3x). The organic substances were combined, washed with water, saturated saline solution, dried over Ma»5O»5x and evaporated to dryness. Purification by column chromatography using a gradient of 0-5095 ethyl acetate in hexanes afforded 2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)-M-(3-sulfamoylphenyl)-benzamide (710 mg, 8695 ) in the form of a white solid. Mass/charge according to E5I-M5: calculated 412.03165, found 413.3 (Mn).

Holding time: 1.5 minutes.

Co., Ltd.) EXAMPLE 17

Preparation of 4,5-dichloro-2-fluoro-M-(3-sulfamoylphenyl)benzamide

A. si u si MN s E oo si E

I00246| A solution of 3-aminobenzenesulfonamide (271.9 mg, 1.58 mmol), 4,5-dichloro-2-fluorobenzoic acid (300 mg, 1.43 mmol) and NATI (654.8 mg, 1.72 mmol) in OME (3.12 ml) was treated with M-methylmorpholine (315.5 μl, 2.87 mmol) and stirred at 40 "C for 16 hours. The reaction mixture was diluted with ethyl acetate and water, and the organic layer was separated.

The organic layer was washed with 1N HCl, water (3x50 ml) and saturated saline, then dried over Mag5O54, filtered and concentrated. The precipitate was suspended in dichloromethane to give a white precipitate. The precipitate was filtered and washed with dichloromethane to give 4,5-dichloro-2-fluoro-N-(3-sulfamoylphenyl)benzamide (422 mg, 8195) as a white powder. "H-NMR (400 MHz, OM50O-av) b 10.85 (s, 1H), 8.32-8.25 (m, 1H), 8.03 (d, 9U-6.7 Hz, 1H) , 7.93 (d, 9-9.5 Hz, 1H), 7.83 (dt, U-6.8, 2.2 Hz, 1H), 7.64-7.52 (m, 2H), 7.42 (s, 2H) m.h. Mass/charge according to EBI-Me: calculated 361.96948, detected 364.7 (M-a-1)7; Retention time: 1.4 minutes (passage of 3 minutes) .

EXAMPLE 18

Preparation of 2-fluoro-M-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)-benzamide

SEZ O SEZ O in "Me

EZS E oo EZS E

(00247| To 3-aminobenzenesulfonamide (300.8 mg, 1.75 mmol) in methyl tert-butyl ether (2.8 mL) was added CoCO3 (689.9 mg, 5.0 mmol) in water (2, The reaction mixture was stirred at room temperature, and 2-fluoro-4,6-bis(trifluoromethyl)benzoyl chloride (490 mg, 1.66 mmol) in methyl tert-butyl ether (2.8 mL) was added over drops. The reaction mixture was stirred at room temperature for 40 min. Ethyl acetate (50 mL) was added, and the organic layer was separated, washed with brine, and concentrated to give 2-fluoro-N-(3-sulfamoylphenyl)-4,6-bistrifluoromethyl) benzamide (162 mg, 2395) as a pink solid, which was used in the next step without further purification. "H-NMR (400 MHz, OM50-av) 6 11.27 (s, 1H), 8.49-8.35 (m, 1H), 8.31-8.08 (m, 2H), 7, 74 (dt, 97.5, 1.9 Hz, 1H), 7.69-7.54 (m, 2H), 7.46 (s, 2H) m.h.

EXAMPLE 19

Preparation of 2,4-dichloro-6-fluoro-M-(3-sulfamoylphenyl)benzamide so si o СХ

MN

"At sia goke so v uva: oo s E oo si E

I(00248| To a solution of 2,4-dichloro-b6-fluorobenzoic acid (400 mg, 1.91 mmol), 3-aminobenzenesulfonamide (329.6 mg, 1.91 mmol) and NATI (727.8 mg, 1, 91 mmol) in OME (4 mL) was added M-methylmorpholine (210.4 μL, 1.91 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into 1N NaCl and extracted with ethyl acetate (3x). the substances were combined, washed with 1N MEDIA, water, saturated saline solution, dried over Mag250", filtered and evaporated to dryness. Purification by means of column chromatography using a gradient of ethyl acetate in hexanes 1-50905 gave 2,4-dichloro-6-fluorine -M-(3-sulfamoylphenyl)benzamide (420 mg, 6095”) as a white solid.

EXAMPLE 20

Preparation of 2-cyclopropyl-6-fluoro-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide

E O o Sx "MN" uva oon oo N oo

B EzS E oo EzS E (00249) To the mixture of 2,6-difluoro-4-(trifluoromethyl)benzoic acid (500 mg, 2.21 mmol) in

To TNE (4.0 mL) was slowly added bromo(cyclopropyl)magnesium (12.0 mL 0.5M, 6.00 mmol). The reaction mixture was stirred at room temperature for one hour, then at 557 for one hour. Additional bromo(cyclopropyl)magnesium (8.84

Zo ml 0.5M, 4.42 mmol), and the reaction mixture was stirred at 55 °C for 12 additional hours.

The reaction mixture was carefully poured into 50 ml of saturated MNACI1 and extracted with ethyl acetate.

The organic layer was washed with water. The combined aqueous layers were acidified to pH-3 using 1N CARRIER and extracted with ethyl acetate (2x50 ml), dried over sodium sulfate, filtered and concentrated to give 2-cyclopropyl-b6-fluoro-4-(trifluoromethyl)benzoic acid (345 mg , 6395), which was used at the next stage without additional purification. Mass/charge by

E5BI-M5: calculated 248.05, detected 249.15 (May1). Hold time: 0.59 minutes (1 minute skip). "H-NMR (400 MHz, OM50-av) b 7.91-7.43 (m, 1H), 7.12 (s, 1H), 2.04 (tt, 98.4, 5.2 Hz, 1H), 1.09-0.98 (m, 2H), 0.89-0.80 (m, 2H) ppm (00250) 2-Cyclopropyl-6-fluoro-4-(trifluoromethyl)benzoic acid (345 mg, 1.39 mmol), toluene (3.4 mL), and pyridine (5.6 μL, 0.069 mmol) were added to the reaction vessel, and the mixture was heated to 60 °C under an inert atmosphere. 5OCI»g (202.8 μl, 2.780 mmol) was added to the reaction mixture, and the mixture was stirred for 90 minutes. Additional OCI (900 μl, 12.34 mmol) was added and the mixture was concentrated in vacuo. Toluene was added, and the mixture was concentrated again to give the product, which was used in the next step without further purification. 00251) To 3-aminobenzenesulfonamide (271.4 mg, 1.576 mmol) in methyl tert-butyl ether (1.99 ml) and OME (1 ml) was added K»CO3 (544.4 mg, 3.94 mmol) in water (1.99 ml).

The reaction mixture was stirred at room temperature, and 2-cyclopropyl-b-fluoro-4-(trifluoromethyl)benzoyl chloride (350 mg, 1.31 mmol) in methyl tert-butyl ether (1.99 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight, after which 50 ml of ethyl acetate was added. The 2 layers were separated, and the organic layer was washed with saturated saline, dried with Md2O, filtered and concentrated to give 2-cyclopropyl-6-fluoro-M-(3Z-sulfamoylphenyl)-4-bo

(trifluoromethyl)benzamide (220 mg, 4295) as a pink solid, which was used in the next step without further purification. Mass/charge by E5I-M5: calculated 402.07, found 403.1 (M--1)". Retention time: 0.59 minutes (passing 1 minute).

EXAMPLE 21

Preparation of /2-(2-chloro-4-fluorophenoxy)-M-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide (33)

SEZ of the Russian Federation

I'm standing" (c) og

IS

I(00252| To a solution of 2-chloro-4-fluorophenol (21 g, 143.1 mmol) and 2-fluoro-6-(trifluoromethyl)benzaldehyde (25 g, 130.1 mmol) in OME (125.0 ml) C52CO3 (46.6 g, 143.1 mmol) was added, and the reaction mixture was stirred at 100 "C for 1 hour. The mixture was poured into water (500 ml) and extracted with ethyl acetate (3x150 ml). The organic substances were combined, washed with water , saturated saline solution (2x), dried over Mag5O»4, filtered and evaporated to give a red oil, which solidified after standing overnight. The material was then triturated with hot hexanes and cooled to 25°C. The suspension was filtered and washed with cold hexanes to give 2-(2-chloro-4-fluorophenoxy)-6-(trifluoromethyl)benzaldehyde (32.7 g, 7995) as an off-white solid. "H-NMR (400 MHz, OM50O-av) 6 10.61 (s, 1H), 7.84-7.70 (m, 2H), 7.66 (d, 9-7.9 Hz, 1H), 7.47 (dd, 9-9.0, 5.3 Hz, 1H), 7.42-7.32 (m, 1H), 7.12 (d, 9-8.3 Hz, 1H) ppm 00253) To a solution of 2-(2-chloro) -4-fluorophenoxy)-6-(tr fluoromethyl)-benzaldehyde (31 g, 97.3 mmol) in 155.0 mL of NH4OH (155.0 mL), water (100.8 mL), SNHCM (155.0 mL), and 2-methyl-2-butene (51.45 mL , 486.4 mmol) sodium dihydrogen phosphate (18.3 ml, 291.9 mmol) was added, and the mixture was cooled to 0 "C. Sodium chlorite (26.40 g, 291.9 mmol) was added in one portion, and the mixture was stirred at 25°C for 1 hour. The pH of the mixture was adjusted to 2-3 with 1N He, and the layers were separated.

The aqueous layer was extracted with ethyl acetate (3x). All organic layers were combined, and solid sodium sulfite (5 g), then saturated saline solution (50 ml) and 1N mMon (10 ml) were added to a separatory funnel, and the mixture was shaken until the yellow color disappeared. The layers were separated and the organic layer was washed with saturated brine, dried over Ma»5O, filtered through a short plug of silica gel and evaporated to dryness to give 2-(2-chloro-4-

From fluorophenoxy)-6-(trifluoromethyl)benzoic acid (40 g, 9895) in the form of oil, which was used in the next stage without additional purification. Mass/charge by E5I-M5: calculated 334.00, detected 335.1 (M--1)". Retention time: 1.78 minutes (passing Z

minutes).

И(00254|) NATI (16.36 g, 43 .03 mmol), then 3-aminobenzenesulfonamide (9.88 g, 57.37 mmol) and M-methylmorpholine (10.51 ml, 95.60 mmol), and the mixture was heated to 80 "C and stirred at this temperature for 4 hours. 3-aminobenzenesulfonamide (4.12 g, 23.91 mmol) was re-charged into the reaction mixture, stirred at 80 °C for 13 hours. The mixture was poured into 1N HCl (400 ml) and extracted with ethyl acetate (3x200 ml). Organic substances were combined, washed with 1N HCl (2 x 400 ml), water (2 x 400 ml), saturated saline, and then dried over Mag25O", filtered and evaporated to dryness to give a crude mixture, which was purified by silica gel column chromatography using gradient of ethyl acetate and hexanes (0-5095) to give the desired product as a white foam.After drying in vacuo, 2-(2-chloro-4-fluorophenoxy)-M-(3-sulfame ylphenyl)-6-(trifluoromethyl)benzamide (33) (14 g, 6095) was obtained as a white solid. Mass/charge according to EBI-M5: calculated 488.02, found 489.3 (M--1)7. Dwell time: 1.57 minutes (skip from 1 minute). "H-NMR (400 MHz, OM50O-av) b 11.02 (s, 1H), 8.29 (s, 1H), 7.73 (d, 927.3 Hz, 1H), 7.69-7 .60 (m, ZN), 7.59-7.51 (m, 2H), 7.41 (s, 2H), 7.38-7.29 (m, 2H), 7.10 (d, 9 -7.3 Gu, 1H) m.h.

EXAMPLE 22

Preparation of 2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide (13)

Oh Me! (c) p

IS

(00255) 2-Fluoro-M-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide (130 mg, 0.36 mmol), 4-fluoro-2-methoxyphenol (204.5 μL, 1.8 mmol) and C52bOz (584.5 mg, 1.8 mmol) in MMR (1 mL) was stirred at 90 "C for 4 hours. The reaction mixture was poured into 1N HCl and extracted with ethyl acetate (3x). The organic substances were combined, washed with water, saturated saline solution, dried with Mag50O»x and evaporated to dryness. Purification by reverse-phase HPLC using a gradient (1-9995 ASM in water (NSI modifier)) gave /2-(4-fluoro-2-methoxyphenoxy)-M-( 3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide (13) (25.6 mg, 1495) as a white solid. Mass/charge by E5I-M5: calculated 484.07, found 485.3 (M'-1 )7. Retention time: 1.61 minutes (3 minute skip). "H-NMR (400 MHz, OM50-a4v) 6 10.98 (s, 1H), 8.33 (s, 1H), 7.79 -7.72 (m, 1H), 7.61-7.48 (m, 4H), 7.40 (s, 2H), 7.20 (dd, 9U-8.9, 5.9 Hz, 1H ), 7.14 (dd, U-10.7, 2.9 Hz, 1H), 6.93 (d, 9U-8.3 Hz, 1H), 6.84 (td, U-8.4 , 2.8

Hz, 1TN), 3.77 (s, ZN) m.h.

I00256| Following a method similar to that described above for compound (13), the following compounds were prepared from 2-fluoro-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide and phenol. 2-(4-fluoro-2-methylphenoxy)-IM-(3-12 sulfamoylphenyl)-6-4-fluoro-2-methylphenol trifluoromethyl)benzamide 2-(2-methoxyphenoxy)-M-(3-57 sulfamoylphenyl)- 6-2-methoxyphenol (trifluoromethyl)benzamide 2-(4-chloro-2-methylphenoxy)-IM-(3-58 sulfamoylphenyl)-6- 4-chloro-2-methylphenol (trifluoromethyl)benzamide 2-(3-fluoro- 2-methylphenoxy)-IM-(3-sulfamoylphenyl)-6-3-fluoro-2-methylphenol (trifluoromethyl)benzamide

M-(3-sulfamoylphenyl)-2-(4- (trifluoromethoxy)phenoxy)-6-4-«(trifluoromethoxy)phenol (trifluoromethyl)benzamide 2-(3-fluoro-4-methoxyphenoxy)-M-(3- 61 sulfamoylphenyl)-6-3-fluoro-4-methoxyphenol (trifluoromethyl)benzamide b-(trifluoromethyl)benzamide 2-(2-chloro-4-methoxyphenoxy)-M-(3-75 sulfamoylphenyl)-6-2-chloro-4 -methoxyphenol (trifluoromethyl)benzamide

EXAMPLE 23

Preparation of 2-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide (1)

their

MN

M. V

But oh "oh

EzS (6)

IS

(00257) 2-Fluoro-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide (32.2 mg, 0.1 mmol), 4-fluorophenol (112.1 mg, 1 mmol) was dissolved in OME (1 ml). C52CO3 (325.8 mg, 1 mmol) was added and the reaction mixture was heated at 100 °C for 1 hour. The reaction mixture was filtered and purified by reversed-phase preparative HPLC using a gradient of 10-9995 acetonitrile in water (HCl as modifier) to give 2-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide (1) (25.6 mg, 5695). Mass/charge by E5I-M5: calculated 454.06, found 455, 3 (M--1)". Dwell time: 1.96 minutes (skip from 1 minute). "H-NMR (400 MHz, OM50O-av) b 10.84 (s, 1H), 8.34-8.24 (m, 1H), 7.88 (d, 9-7.9 Hz, 1H) , 7.82-7.72 (m, 1H), 7.64 (dd, 9-7.9, 0.8 Hz, 1H), 7.60-7.47 (m, 2H), 7.40 (c, 2H), 7.32-7.25 (m, 2H), 7.25-1.18 (m, 2H), 7.15 (c, 1H) ppm (00258 | Following the method, similar to that described above for compound (1), the following compounds were obtained starting with 2-fluoro-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide and the following phenols.

Product name 2-(2,4-difluorophenoxy)-M-(3- 2 sulfamoylphenyl)-4-(trifluoromethyl)benzamide 2,a-difluorophenol 2-(4-fluoro-2-methoxyphenoxy)-M-(3- And c. 14 sulfamoylphenyl)-4-(trifluoromethyl)benzamide 4-fluoro-2-methoxyphenol 2-(4-fluoro-2-methylphenoxy)-IM-(3- and c. 18 sulfamoylphenyl)-4-(trifluoromethyl)benzamide 4-fluoro-2-methylphenol 2-(4-chloro-2-methoxyphenoxy)-M-(3- I v. 42 sulfamoylphenyl)-4-(trifluoromethyl)benzamide a-chloro-2-methoxyphenol 2-(3-fluoro -4-methoxyphenoxy)-M-(3-Sulfamoylphenyl)-4-(trifluoromethyl)benzamide 3-fluoro-4-methoxyphenol 44 2g-(2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-2-methoxyphenol 4-(trifluoromethyl)benzamide 2-(4-ethoxyphenoxy)-M-(3-sulfamoylphenyl)-4- 4-ethoxyphenol (trifluoromethyl)benzamide 00046000 ooepropoxyphenoxy MU - T2-(2-propoxy)phenol sulfamoylphenyl)-4-(trifluoromethyl) ) benzamide

M-(3-Sulfamoylphenyl)-2-(O-tolyloxy)-4-Y 47 (trifluoromethyl)benzamide 2-methylphenol 2-(2-chloro-4-methoxyphenoxy)-M-(3-Y MY 48 Sulfamoylphenyl)- 4-"(trifluoromethyl)benzamide 2-xpor-4-methoxyphenol 2-(4-methoxy-2-methylphenoxy)-M-(3- I v. 49 sulfamoylphenyl)-4-(trifluoromethyl)benzamide 4-methoxy-2- methylphenol 2-(2,4-dimethoxyphenoxy)-M-(3-H sulfamoylphenyl)-4-(trifluoromethyl)benzamide 2,4-dimethoxyphenol

M-(3-sulfamoylphenyl)-2-(4-51 (trifluoromethoxy)phenoxy)-4-4-(trifluoromethoxy)phenol (trifluoromethyl)benzamide 2-(3-fluoro-2-methoxyphenoxy)-M-(3- c. z2 sulfamoylphenyl)-4-(trifluoromethyl)benzamide 3-fluoro-2-methoxyphenol 2-(4-isopropoxyphenoxy)-M-(3-: 53 sulfamoylphenyl)-4-(trifluoromethyl)benzamide 4-isopropoxyphenol 2-(3 -chloro-4-methoxyphenoxy)-M-(3- I 67 sulfamoylphenyl)-4-(trifluoromethyl)benzamide 3-chloro-4-methoxyphenol

Product name 2-(3-Chloro-2-methoxyphenoxy)-M-(3-I vv sulfamoylphenyl)-4-(trifluoromethyl)benzamide 3-Chloro-2-methoxyphenol 2-(2-chlorophenoxy)-M-( 3-sulfamoylphenyl)-4- 73 (trifluoromethyl)benzamide 2-chlorophenol

EXAMPLE 24

Preparation of 5-chloro-2-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)benzamide (5) in

SI "MN on oo and (9,

IS

(00259) 5-Chloro-2-fluoro-M-(3-sulfamoylphenyl)benzamide (32.8 mg, 0.1 mmol), 4-fluorophenol (35.8 mg, 0.3 mmol) was dissolved in MMR (0 .5 ml). C52CO3 (98 mg, 0.3 mmol) was added, and the reaction mixture was heated at 90 C for 6 hours. The reaction mixture was filtered and purified by reversed-phase preparative HPLC using a gradient of 10-9995 acetonitrile in water (HCl as modifier) to give 5-chloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide (5) ( 10.2 mg, 2495). Mass/charge according to E5BI-M5: calculated 420.03, found 421.1 (M--1)". Retention time: 1.70 minutes (passing 3 minutes).

I00260| Following a method similar to that described above for compound (5), the following compounds were obtained.

Product name Aryl fluoride z-chloro-2-(4-fluoro-2-B-chloro-2-fluoro-M-(3-4-fluoro-2-16 methoxyphenoxy)-M-(3-sulfamoylphenyl)benzami methoxyphenol sulfamoylphenyl) benzamide U d z-chloro-2-(a-chloro-4-B-chloro-2-fluoro-M-(3-2-chloro-4-17 fluorophenoxy)-M-(3- sulfamoylphenyl)benzami fluorophenol sulfamoylphenyl) benzamide U d R z-chloro-2-(4-fluoro-2-B-chloro-2-fluoro-M-(3-4-fluoro-2-20 methylphenoxy)-M-(3-sulfamoylphenyl)benzami methylphenol sulfamoylphenyl )benzamide In d

EXAMPLE 25

Preparation of 2-(2-chloro-4-fluorophenoxy)-6-methyl-M-(3-sulfamoylphenyl)-benzamide (38)

Her fe

MN so oo i 0) su i

IS

I00261| To a solution of 2-fluoro-6-methylbenzaldehyde (1.1 g, 7.75 mmol) and 2-chloro-4-fluorophenol (817.7 μl, 7.75 mmol) in OME (9.2 ml) was added cesium carbonate (2.5 g, 7.75 mmol) and the mixture was heated at 100 °C for 1 h. The mixture was cooled to room temperature before being diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organic the layers were washed with saturated saline, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography using a gradient of ethyl acetate in hexanes (0-

10095) to give 2-(2-chloro-4-fluorophenoxy)-6-methylbenzaldehyde (1.05 g, 5195). Mass/charge according to E5BI-M5: calculated 264.03, found 265.1 (Ma-1):. Dwell time: 2.02 minutes (skip from 1 minute). (00262) To a solution of 2-(2-chloro-4-fluorophenoxy)-6-methylbenzaldehyde (1.05 g, 3.97 mmol) in

Sodium dihydrogen phosphate (745.7 μl, 11.90 mmol), 2-methylbut-2-ene (2.1 ml , 19.83 mmol) and sodium chlorite (1.08 g, 11.90 mmol).

The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was acidified with 1N HCl and diluted with ethyl acetate. Sodium sulfite was added to remove the faint yellow color. The two layers were separated and the aqueous layer was extracted with ethyl acetate (3x). The organics were combined, washed with saturated saline solution, dried over sodium sulfate, filtered and concentrated to obtain 2-(2-chloro-4-fluorophenoxy)-b-methylbenzoic acid (1.06 g, 9595). Mass/charge according to E5I-M5: calculated 280 .03, detected 281.5 (M--1) 7. Retention time: 1.7 minutes (3 minute pass).

I00263| OME (1.4 μl, 0.018 mmol) was added to a mixture of 2-(2-chloro-4-fluorophenoxy)-6-methylbenzoic acid (100 mg, 0.36 mmol), SNesi" (2.0 ml) and OSI" (33.8 μl, 0.46 mmol) at room temperature. The mixture was stirred for 1.5 hours before its concentration under reduced pressure. The precipitate was placed under high vacuum for 30 min before it was taken up in CHN (2.0 mL) and added to a mixture of 3-aminobenzenesulfonamide (92.0 mg, 0.53 mmol), EM (86.5 µL, 1 .07 mmol) and СНоСи» (2.0 ml) at room temperature.

Stirring of the mixture was ensured for 2 hours at room temperature before its distribution between 1H НС and СНоСи". The layers were separated, and the organic layer was washed with saturated saline, dried over sodium sulfate, filtered and concentrated under reduced pressure. The precipitate was subjected to preparative HPLC (10-9095 AFM/water with 0.0195 NH) to give 2-(2-chloro-4-fluorophenoxy)-6-methyl-M-(3-sulfamoylphenyl)benzamide (38) (6.5 mg, 490). Mass/charge according to EBI-M5: calculated 434.05, found 435.5 (M'n1)7. Dwell time: 1.72 minutes (skip from 1 minute). "H-NMR (400 MHz, OM50O-av) b 10.83 (s, 1H), 8.41-8.36 (m, 1H), 1.16 (dt, 97.1, 2.0 Hz, 1H), 7.63-7.51 (m, ЗН), 7.39 (s, 2Н), 7.34-7.25 (m, ЗН), 7.12-7.07 (m, 1Н) , 6.61 (t, U-8.0 Hz, 1H), 2.35 (s, ЗН) m.h.

EXAMPLE 26

Preparation of 2-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide (3) in

IF)

IS

I00264| A mixture of 2-fluoro-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide (9.0 g, 24.8 mmol), 4-fluorophenol (8.4 g, 74.5 mmol), cesium carbonate (24 .3 g, 74.5 mmol) and OME (225.0 mL) were heated at 100 °C for 0.5 h. The mixture was cooled to room temperature before partitioning between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate ( 3x). The combined organic layers were washed with sat. off-white solid. The solid was suspended in hexane, then filtered. This solid was suspended in diethyl ether and filtered (2x). The solid was placed in vacuo at 557 for 1 hour to give 2-(4-Fluorophenoxy)- M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide (3) (8.6 g, 7790). Mass/charge according to E5I-M 5: calculated 454.06, detected 455.5 (М--1)". Dwell time: 1.87 minutes (skip from 1 minute). "H-NMR. (400

MHz, OM50O-av) b 10.81 (s, 1H), 8.30 (s, 1H), 8.01 (d, U-2.1 Gu, 1H), 7.82 (ddd, 9U-8 ,9, 4.8, 2.2 Hz, 2H), 7.61-7.49 (m, 2H), 7.40 (s, 2H), 7.35-7.23 (m, 4H), 7.00 (d, 9-8.7 Gu, 1H) m.h.

EXAMPLE 27

Preparation of 2-(4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide (25)

and (about)

Nzo. at

IS

(00265) To a mixture of 2-fluoro-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)-benzamide (10 g, 27.60 mmol) in OME (55.00 mL) was added 4-fluoro-2-methylphenol ( 3.7 g, 28.98 mmol) and cesium carbonate (10.8 g, 33.12 mmol), and the mixture was heated at 100 °C for 1 hour. The mixture was cooled to ambient temperature and diluted with 300 mL of ice water. acidified with BN HCl and diluted to a volume of 400 ml with water. The suspension was diluted with 400 ml of ethyl acetate, and the organic phase was separated. The organic phase was washed with 400 ml of water, and then with 400 ml of saturated saline. The organic phase was dried over NaClO". filtered and concentrated in vacuo. The crude solid was diluted in 100 ml of acetonitrile and heated to homogeneity. The mixture was stirred at 25 "C, the precipitate was collected by filtration and washed with 25 ml of acetonitrile to give / 2-(4-fluoro-2-methylphenoxy)-M -(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide (25) (4.14 g, 3295). Mass/charge according to E5I-M5: calculated 468.08, found 469.20 (M.-1)-. Dwell time: 1.81 minutes (skip from 1 minute). "H-NMR (400 MHz, OM50O-av) b 10.83 (s, 1H), 8.33 (s, 1H), 8.01 (d, 9-21 Hz, 1H), 7.81 (m , 2H), 7.56 (m, 2H), 7.40 (s, 2H), 7.23 (ddd, 9U-13.9, 9.1, 4.0 Hz, 2H), 7.14 ( td, 9-86, 3.1 Hz, 1H), 6.82 (d, 9-8.7 Hz, 1H), 2.15 (s, ЗН) m.ch.

EXAMPLE 28

Preparation of /2-(2-chloro-4-fluorophenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide (26)

Her, 0, es zve

No, no; iv)

IS

I00266| A mixture of 2-fluoro-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide (15 g, 41.40 mmol), 2-chloro-4-fluorophenol (17.35 g, 118.4 mmol), cesium carbonate (40.47 g, 124.20 mmol) and

OME (375.0 mL) was heated at 100 °C for 1 h 15 min. The mixture was cooled to room temperature and filtered using ethyl acetate. Water was added to the filtrate. The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). the combined organic layers were washed with sat. , containing the desired

The product was concentrated, and the resulting solid was suspended in ether and hexanes and filtered. The solvent was evaporated under reduced pressure to give 2-(2-chloro-4-fluorophenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide (26) (10.35 g, 5095) as a pale pink solid substances Mass/charge according to E5I-M5: calculated 488.02, found 489.2 (M--1)7. Dwell time: 2.03 minutes (skip from 1 minute). "H-NMR (400 MHz, OM50O-av) b 10.83 (s, 1H), 8.37-8.27 (m, 1H), 8.04 (d, 9-2.1 Hz, 1H) , 7.92-7.74 (m, 2H), 7.69 (dd, 9U-8.4, 3.0 Hz, 1H), 7.63-7.50 (m, 2H), 7.50 -7.28 (m, 4H), 6.92 (d, 9-8.7 Hz, 1H) m.h.

I00267| Following a method similar to that described above for compound (26), the following compounds were prepared starting with 2-fluoro-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide and the phenols listed below.

Name of the product

M-(3-sulfamoylphenyl)-2-(O-tolyloxy)-5-Y 32 (trifluoromethyl)benzamide O cresol for 2g-(2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-5-2-methoxyphenol (trifluoromethyl )benzamide 29 2-(4-methoxyphenoxy)-M-(3-sulfamoylphenyl)-5-4-methoxyphenol (trifluoromethyl)benzamide 24 2-(4-chlorophenoxy)-M-(3-sulfamoylphenyl)-5-4-chlorophenol (trifluoromethyl)benzamide 2-(2,5-difluorophenoxy)-M-(3-sulfamoylphenyl)-5-Y (trifluoromethyl)benzamide 2,5-difluorophenol 23 2-(4-ethoxyphenoxy)-M-(3-sulfamoylphenyl) )-5- 4-ethoxyphenol (trifluoromethyl)benzamide 2-(d4-chloro-2-methylphenoxy)-M-(3-sulfamoylphenyl)-5- 4-chloro-2-methylphenol trifluoromethyl)benzamide 2-(3-fluoro- 2-methoxyphenoxy)-M-(3-1 in. 23 sulfamoylphenyl)-5-(trifluoromethyl)benzamide 3-fluoro-2-methoxyphenol 2-(4-fluoro-2-methoxyphenoxy)-M-(3-1 in 21 sulfamoylphenyl)-5-(trifluoromethyl)benzamide 4-fluoro-2-methoxyphenol 2-(3-fluoro-4-methoxyphenoxy)-M-(3-Y 28 sulfamoylphenyl)-5-(trifluoromethyl)benzamide 3-fluoro- 4-methoxyphenol 37 2-(4-isopropoxyphenoxy)-M-(3-sulfamoylphenyl)-5- 4-isopropoxyphenol (trypto pmethyl)benzamide 2-(2,4-dimethoxyphenoxy)-M-(3-sulfamoylphenyl)-5-Y 36 (trifluoromethyl)benzamide 2,4-dimethoxyphenol 2-(4-chloro-g-methoxyphenoxy)-M-(Z -sulfamoylphenyl)-| in. 35 c-(trifluoromethyl)benzamide 4-chloro-2-methoxyphenol 34 2g-(2-chloro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)- 2-chloro-4-methoxyphenol 5-(trifluoromethyl)benzamide 2- (4-(difluoromethoxy)phenoxy)-M-(3-ІІ

M sulfamoylphenyl)-5-(trifluoromethyl)benzamide 4-(difluoromethoxy)-phenol

M-(3-sulfamoylphenyl)-2-(4- 39 (trifluoromethoxy)phenoxy)-5- 4-(trifluoromethoxy)-phenol (trifluoromethyl)benzamide

EXAMPLE 29

Preparation of 5-fluoro-2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-benzamide (21)

E «MN about oo and (6) ot

IS

(00268) To a solution of 2,5-difluoro-M-(3-sulfamoylphenyl)benzamide (200 mg, 0.64 mmol) in OME (2 mL) was added 4-fluoro-2-methoxyphenol (72.99 μL, 0, 64 mmol) and cesium carbonate (1.0 g, 3.2 mmol), and the mixture was heated at 100 °C for 3 hours. The reaction mixture was cooled to 25 °C, diluted with ethyl acetate and poured into water. The 2 layers were separated, and the aqueous layer extracted with ethyl acetate (2x). The organics were combined, dried over Md5oOx", filtered and evaporated to give a red oil, which was purified by column chromatography using a gradient of ethyl acetate and hexanes to give 5-fluoro-2-(4-fluoro -2- methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide (21) (7.2 mg, 395). Mass/charge by E5I-M5: calculated 434.07, found 435.3 (M-ya-1) -. Retention time: 1.8 minutes (3 minute skip). "H-NMR (400 MHz, OM50-av) b 10.64 (s, 1H), 8.31 (s, 1H), 7.80 ( d, U-6.2 Hz, 1H), 7.52 (m,

ЗН), 7.39 (с, 2Н), 7.29 (dd, 9U-11.2, 5.7 Hz, 1Н), 7.19 (dd, У-8.4, 5.8 Hz, 1Н ), 7.10 (m, 1H), 6.78 (m, 2H), 3.74 (s, ЗН) m.h.

EXAMPLE 30

Preparation of 4-cyano-2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide (10) 1

MN soy oo

Mo about Art

IS

00269) To a solution of 4-cyano-2-fluoro-M-(3-sulfamoylphenyl)benzamide (19.2 mg, 0.06 mmol) and 4-fluoro-2-methoxyphenol (42.6 mg, 0.3 mmol) C52CO3 (97.7 mg, 0.3 mmol) was added to MMR (0.5 ml), and the mixture was stirred at 90 C for 4 hours. The reaction mixture was filtered and purified by reversed-phase HPLC using a gradient of acetonitrile in water (1-9995) to give 4-cyano-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide.

Mass/charge according to E5BI-M5: calculated 441.08, detected 442.3 (M.-1)". Retention time: 1.53 minutes (passage of 3 minutes).

I00270| Following a method similar to that described above for compound (10), the following compounds were prepared starting from 4-cyano-2-fluoro-N-(3-sulfamoylphenyl)benzamide and the phenols listed below.

Product name 2-(2-Chloro-4-fluorophenoxy)-4-cyano-M-(3-M 4 sulfamoylphenyl)benzamide 2-xpro-4-fluorophenol 4-cyano-2-(4-fluoro-2-methylphenoxy) )-IM-(3- І c.

Es sulfamoylphenyl)benzamide 4-fluoro-2-methylphenol

EXAMPLE 31

Preparation of 2-(2-chloro-4-fluorophenoxy)-5-cyano-M-(3-sulfamoylphenyl)-benzamide (11)

Mo MN uva; oho and (c)

IS

00271) To a solution of 5-cyano-2-fluoro-M-(3-sulfamoylphenyl)benzamide (31.9 mg, 0.10 mmol) and 2-chloro-4-fluorophenol (44.0 mg, 0.30 mmol) C52CO3 (97.7 mg, 0.30 mmol) was added to MMP (0.5 ml), and the mixture was stirred at 90 C for 4 hours. The reaction mixture was filtered and purified by reversed-phase HPLC using a gradient of acetonitrile in water (1-9995) using NCI as a modifier to give 2-(2-chloro-4-fluorophenoxy)-5-cyano-

M-(3-sulfamoylphenyl)benzamide (11) (5.8 mg, 1395). Mass/charge according to E5I-M5: calculated 445.03, found 446.1 (M.-1)". Retention time: 1.57 minutes (transmission of 3 minutes). "H-NMR (400 MHz, OM50-av) 5 10.84 (s, 1H), 8.33 (s, 1H), 8.20 (d, 9-2.0 Hz, 1H), 7.92 (d, 9-8.7 Hz, 1H) , 7.81 (d, U-6.9 Hz, 1H), 7.69 (dd, U-8.3, 2.8 Hz, 1H), 7.60-7.54 (m, 2H), 7.48 (dd, 929.1, 5.2 Hz, 1H), 7.44-

From 7.34 (m, ZN), 6.88 (d, U-8.7 Hz, 1H) m.h.

EXAMPLE 32

Preparation of 4-chloro-2-(4-fluorophenoxy)-5-methyl-M-(3-sulfamoylphenyl)-benzamide (7)

they are not MN

No

SI (F)

IS

I00272| To a solution of 5-bromo-4-chloro-2-fluoro-M-(3-sulfamoylphenyl)benzamide (122.3 mg, 0.3 mmol) and 4-fluorophenol (100.9 mg, 0.9 mmol) in M Cesium carbonate (293.2 mg, 0.9 mmol) was added to M-dimethylformamide (3 ml), and the reaction mixture was heated at 100 "C for 2 hours.

The reaction mixture was filtered and purified by reversed-phase preparative chromatography using a gradient of 20-9995 acetonitrile in water containing HCl as a modifier to give 5-bromo-4-chloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl) )benzamide (59.5 mg, 4095). (00273) To 5-bromo-4-chloro-2-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)-benzamide (44 mg, 0.09 mmol), methylboronic acid (7.9 mg, 0.13 mmol), tetrakis(triphenylphosphine)palladium(O) (5.3 mg, 0.004 mmol) and 1,2-dimethoxyethane (500 μl), sodium carbonate (132.1 μl of a 2M solution, 0.26 mmol) was added and the reaction mixture was heated at 80 "C for 65 hours. The reaction mixture was filtered and the solvent was evaporated. The crude product was purified by reversed-phase I CM5 using acetonitrile and water containing NCI as a modifier to give 4-chloro-2-(4-fluorophenoxy)- 5-Methyl-M-(3-sulfamoylphenyl)benzamide (7) (12.1 mg, 29965) as a yellow solid. Mass/charge by E5I-M5: calcd 434.05, found 435.15 (M-- 1)". Holding time: 1.8 minutes (skip from 1 minute). "H-NMR (400 MHz,

OM50-dv) b 10.65 (s, 1H), 8.30-8.24 (m, 1H), 7.81-7.72 (m, 1H), 7.68 (s, 1H), 7 .58-7.48 (m, 2H), 7.38 (s, 2H), 7.29-7.18 (m, 2H), 7.18-7.09 (m, 2H), 6.98 (c, 1H), 2.36 (c, ZN) m.h.

EXAMPLE 33

Preparation of 4-chloro-2-(2-chloro-4-fluorophenoxy)-M-(3-sulfamoylphenyl)-benzamide (8)

MN m r:

No

SI (in, p. I

IS

(00274) To a solution of 4-chloro-2-fluoro-M-(3-sulfamoylphenyl)benzamide (39.4 mg, 0.12 mmol) and 2-chloro-4-fluorophenol (52.8 mg, 0.36 mmol) ) in OME (0.8 mL) was added cesium carbonate (117.3 mg, 0.36 mmol), and the reaction mixture was heated at 100 C for 1 hour. The reaction mixture was filtered and purified by reversed-phase preparative chromatography using a gradient of 10-9995 acetonitrile in water containing NCI as a modifier to give 4-chloro-2-(2-chloro-4-fluorophenoxy)-M-(3-sulfamoylphenyl) )benzamide (8) (1.7 mg, 3905).

Mass/charge according to E5I-M5: calculated 454.00, found 455.3 (M.-1)". Retention time: 1.73

From the minute (skip From the minute).

I00275| Following a method similar to that described above for compound (8), the following compounds were prepared starting from 4-chloro-2-fluoro-N-(3-sulfamoylphenyl)benzamide and the phenols listed below.

Product name 4-chloro-2-(4-fluoro-2-methoxyphenoxy)-M-(3- 15 sulfamoylphenyl)benzamide 4-fluoro-2-methoxyphenol 4-chloro-2-(4-fluoro-2- methylphenoxy)-M-(3-Y v. 19 sulfamoylphenyl)benzamide 4-fluoro-2-methylphenol 4-chloro-2-(2,4-dimethoxyphenoxy)-M-(3-Y va sulfamoylphenyl)benzamide 2.,A -dimethoxyphenol

Name of the product 4-chloro-2-(4-chloro-2-methoxyphenoxy)-M-(3-Y v. 85 sulfamoylphenyl)benzamide 4-chloro-2-methoxyphenol a-xpor-2-(h-chloro-4- methoxyphenoxy)-M-(3-2-chloro-4-methoxyphenol sulfamoylphenyl)benzamide 4-chloro-2-(4-isopropoxyphenoxy)-M-(3- : 87 sulfamoylphenyl)benzamide 4-isopropoxyphenol

EXAMPLE 34

Preparation of /- 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-M-(3-sulfamoylphenyl)benzamide (40)

NEBS MN

So oo and (c) o ;SI

IS

(00276) 5-(Difluoromethyl)-2-fluoro-M-(3-sulfamoylphenyl)benzamide (75 mg, 0.22 mmol), 2-chloro-4-fluorophenol (95.7 mg, 0.65 mmol) and cesium carbonate (212.9 mg, 0.65 mmol) in MMP (0.75 mL) was stirred at 90 °C for 2 h. The reaction mixture was diluted with Mehn, filtered, and purified by reversed-phase HPLC using a gradient of acetonitrile in water (1 -9995) and NSI as a modifier to give 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-M-(3-sulfamoylphenyl)benzamide (40) (56 mg, 5395) as a white solid. Mass/charge by

E5BI-M5: calculated 470.03, detected 471.3 (Ma1)-. Dwell time: 1.63 minutes (skip from 1 minute). "H-NMR (400 MHz, OM50-av) b 10.77 (s, 1H), 8.32 (s, 1H), 7.87 (s, 1H), 7.85-7.78 (m, 1H), 7.72-7.64 (m, 2H), 7.60-7.53 (m, 2H), 7.39 (width, ЗН), 7.35 (d, U-8, 1 Hz, 1H), 7.10 (t, 955.8 Gu, 1H), 6.89 (d, 9U-8.5 Hz, 1H) ppm (00277) To 2-fluoro-M-( 3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide (75.7 mg, 0.2 mmol) was added 4-fluoro-2-methoxyphenol (68.3 μl, 0.6 mmol), cesium carbonate (195.5 mg, 0.6 mmol) and

M-methylpyrrolidinone (2 mL), and the reaction mixture was stirred at 100 "C for 30 minutes - 2 hours. The reaction mixture was filtered and the mixture was purified by reversed-phase preparative chromatography using a gradient of 10-9995 acetonitrile in water containing

NSI as a modifier to give 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide (54) (27.8 mg, 2795). Mass/charge according to E5BI-M5: calculated 500.07, detected 501.2 (M--1)y. Hold time: 1.99 minutes (skip from 1 minute). "H-NMR (0M50-dv) 6 10.68 (s, 1H), 8.37-8.30 (m, 1H), 7.84-7.79 (m, 1H), 7.77 (d , 9-8.4 Hz, 1H), 7.60-7.50 (m, 2H), 7.40 (s, 2H), 7.37-7.28 (m, 1H), 7.23- 7.11 (m, 2H), 6.93-6.82 (m, 1H), 6.58-6.50 (m, 1H), 3.75 (s,

ZN) m.ch.

I00278| The following compounds were prepared using an experimental procedure similar to that for compound (54) above, starting with 2-fluoro-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide and the phenols listed below.

Coo)

Product name 2-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)-4-Y 595 (trifluoromethoxy)benzamide 4-fluorophenol 2-(2-chloro-4-fluorophenoxy)-M-(3-sulfamoylphenyl)- | 5. MY 56 4-(trifluoromethoxy)benzamide 2-khpor-4-fluorophenol 2-(2-chloro-4-methoxyphenoxy)-M-(3-MY b2 sulfamoylphenyl)-4-"(trifluoromethoxy)benzamide 2-khpor -4-methoxyphenol 2-(2-chlorophenoxy)-M-(3-sulfamoylphenyl)-4-Y 63 (trifluoromethoxy)benzamide 2-chlorophenol 2-(2-(difluoromethoxy)phenoxy)-M-(3-Yba sulfamoylphenyl) )-4-"(trifluoromethoxy)benzamide 2-(difluoromethoxy)phenol 2-(4-chloro-2-methoxyphenoxy)-M-(3- I v. 65 sulfamoylphenyl)-4-"(trifluoromethoxy)benzamide a-chloro- 2-Methoxyphenol

Product name 2-(3-Chloro-2-methoxyphenoxy)-M-(3-Chloroylphenyl)-4-(trifluoromethoxy)benzamide 3-Chloro-2-methoxyphenol

EXAMPLE 36

Preparation of 2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-M-(3-sulfamoylphenyl)benzamide (70)

MN uva: oho I

PERSONS (c) about "OMe

IS

I00279| 2-Fluoro-4-(1,1,2,2,2-pentafluoroethyl)-M-(3-sulfamoylphenyl)benzamide (34.2 mg, 0.1 mmol), 2-methoxy-4-fluorophenol (34, 2 μL, 0.3 mmol) and C52CO3 (97.8 mg, 0.3 mmol) in MMP (0.4 mL) were stirred at 80°C for 2 h. Purification by HPLC using a gradient of 1-9995 acetonitrile in water, using NCI as a modifier, gave 2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide (70) (17.8 mg, 3395). according to E5BI-M5: calculated 534.07, detected 535.3 (M.-1) 7. Holding time: 1.78 minutes (passing from 3 minutes).

I00280| The following compounds were prepared using an experimental procedure similar to that used for compound (70) above, starting with 2-fluoro-4-(1,1,2,2,2-pentafluoroethyl)-N-(3-sulfamoylphenyl) benzamide and phenols listed below. 2-(4-fluorophenoxy)-4-(perfluoroethyl)-M-(3-Y sulfamoylphenyl)benzamide a-fluorophenol 74 2g-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-M- 4- chloro-2-methoxyphenol

Z-sulfamoylphenyl)benzamide 79 2g-(2-chloro-4-methoxyphenoxy)-4-(perfluoroethyl)-M-2-chloro-4-methoxyphenol

Z-sulfamoylphenyl)benzamide

EXAMPLE 37

Preparation of 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide (7 7) in

SI "MN o oto i

SI (o; od

IS

(002811 4,5-Dichloro-2-fluoro-M-(3-sulfamoylphenyl)benzamide (50 mg, 0.14 mmol), 4-fluoro-2-methoxyphenol (17.3 µL, 0.15 mmol), and CaCO3 (57.1 mg, 0.41 mmol) was combined in OME (0.5 mL) and heated at 75 °C for 12 h. The reaction mixture was filtered and purified by reversed-phase HPLC using a gradient of acetonitrile in water 10- 9995 and 5 mM HCl in the mobile phase to give 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-benzamide (77) (7.5 mg, 1195). /charge on E5BI-M5: calculated 484.01, found 485.3 (M--1)7. Retention time: 1.74 minutes (3 minute skip). "H-NMR (400 MHz, OM50O-av) b 10.70 (s, 1H), 8.33-8.26 (m, 1H), 7.93 (s, 1H), 7.80 (dt, U-6.4, 2.3 Hz, 1H) , 7.60-7.49 (m, 2H), 7.40 (s, 2H), 7.29 (dd, 9U-8.8, 5.8 Hz, 1H), 7.14 (dd, 9 -10.7, 2.9 Gu, 1H), 6.89-6.79 (m, 2H), 3.76 (s, ЗН) m.h.

From I00282| The following compounds were prepared using an experimental procedure similar to that for compound (77) above, starting with 4,5-dichloro-2-fluoro-N-(3-sulfamoylphenyl)benzamide and the phenols listed below.

Product name 4,5-dichloro-2-(2,4-dimethoxyphenoxy)-IM-(3-16 sulfamoylphenyl)benzamide 2,4-dimethoxyphenol 4,5-dichloro-2-(4-fluorophenoxy)-M-( 3- 78 sulfamoylphenyl)benzamide 4-fluorophenol 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-M-(3- 79 sulfamoylphenyl)benzamide 3-fluoro-4-methoxyphenol 4,5- dichloro-2-(4-chloro-2-methoxyphenoxy)-IM-(3-4-chloro-2-methoxyphenol sulfamoylphenyl)benzamide 4,5-dichloro-2-(2-fluoro-4-methoxyphenoxy)-M-( 3- МИ 81 sulfamoylphenyl)benzamide 2-fluoro-4-methoxyphenol 4,5-dichloro-2-(2-chloro-4-methoxyphenoxy)-M-(3- МИ 82 sulfamoylphenyl)benzamide 2-khpor-4- Methoxyphenol 4,5-dichloro-2-(4-fluoro-2-methylphenoxy)-M-(3- I v. 83 sulfamoylphenyl)benzamide 4-fluoro-2-methylphenol

EXAMPLE 38

Preparation of 2-(4-fluoro-2-methoxyphenoxy)-M-(3Z-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide (89)

MN

EzS (9) o"

IS

(00283| To 2-fluoro-M-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide (70 mg, 0.16 mmol) and 4-fluoro-2g-methoxyphenol (20.4 μl, 0, 18 mmol) in OME (68.4 μl) was added K»CO3 (67.5 mg, 0.49 mmol). The reaction mixture was stirred at 70 °C for 2 h, then at 100 °C for 1 h. The reaction mixture was cooled to at room temperature, filtered and purified by reversed-phase HPLC using a gradient of acetonitrile in water (10-9995) to give // 2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4,6-bis (trifluoromethyl)benzamide (89) (44.9 mg, 5095). EBI-M5 mass/charge: calcd 552.06, found 553.2 (M--1)". Retention time: 1.87 minutes (pass WITH

minutes).

I00284| The following compounds were prepared using an experimental procedure similar to that for compound (89) above, starting with 2-fluoro-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide and the phenols listed below.

Product name 2-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)-4,6-bistrifluoromethyl)benzamide 4-fluorophenol 2-(3-fluoro-4-methoxyphenoxy)-M-(3- sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide 3-fluoro-4-methoxyphenol 2-(2-fluoro-4-methoxyphenoxy)-M-(3-Y

With sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide 2-fluoro-4-methoxyphenol 2-(5-fluoro-2-methoxyphenoxy)-M-(3- I v. 32 sulfamoylphenyl)-4,6-bis( trifluoromethyl)benzamide z-fluoro-2-methoxyphenol 2-(4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)-| in. 33 4,6-bis(trifluoromethyl)benzamide 4-fluoro-2-methylphenol

EXAMPLE 39

Preparation of 2,4-dichloro-6-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide (95)

AMN co. o. o. i

SI (0) units

IS

(00285) A mixture of 2,4-dichloro-b6-fluoro-M-(3-sulfamoylphenyl)benzamide (36.3 mg, 0.1 mmol), 4-fluoro-2-methoxyphenol (34.2 μl, 0.30 mmol) and C520Oz (97.7 mg, 0.3 mmol) in MMP (0.4 mL) were stirred for 1 h at 80 °C. The reaction mixture was diluted with methanol, filtered, and purified by reversed-phase HPLC using an acetonitrile/ water (1-9995) and NCI as a modifier to give 2,4-dichloro-6-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide (95) (6.5 mg, 1395) in in the form of a white solid. Mass/charge by E5I-M5: calculated 484.01, found 485.5 (Ma1)-. Retention time: 1.58 minutes (transmission of 3 minutes). "H-NMR (400 MHz, OM50- av)5 11.02 (c, 1H), 8.34 (c, 1H), 7.81-7.74 (m, 1H), 7.61-7.53 (m, 2H), 7.48 (d, 9U-1.8 Gu, 1H), 7.41 (s, 2H), 7.21 (dd, 98.6, 5.8 Hz, 1H), 7.15 (dd, 9U-10, 6, 2.9 Hz, 1H), 6.89-6.81 (m, 1H), 6.60 (d, 9U-1.8 Gu, 1H), 3.78 (s,

ZN) m.ch.

I00286| The following compounds were prepared using an experimental procedure similar to that for compound (95) above, starting with 2,4-dichloro-b-fluoro-M-(3-sulfamoylphenyl)benzamide and the phenols listed below.

Product name 2,4-dichloro-6-(4-fluorophenoxy)-M-(3-Y

For sulfamoylphenyl)benzamide 4-fluorophenol 2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-M-(3- and the same sulfamoylphenyl)benzamide 4-fluoro-2-methylphenol 2,4-dichloro- M-(3-sulfamoylphenyl)-6-(4- 97 (trifluoromethoxy)phenoxy)benzamide 4-(trifluoromethoxy)phenol 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-IM-(3- 4-chloro-2-methoxyphenol sulfamoylphenyl)benzamide 2,4-dichloro-6-(2-fluoro-4-methoxyphenoxy)-M-(3- | 5. MI in sulfamoylphenyl)benzamide 2-fluoro-4-methoxyphenol

EXAMPLE 40

Preparation of 2-cyclopropyl-6-(3-fluoro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide (100) in

MN her V

No

EzC 6)

IS

Ome

I00287| To a mixture of 2-cyclopropyl-6-fluoro-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide (20 mg, 0.08 mmol) and 3-fluoro-4-methoxyphenol (17.7 mg, 0.12 mmol) in OME (0.5 ml) was added

KSO" (41.2 mg, 0.3 mmol), and the reaction mixture was stirred at 100 "C for 2 hours, then at 80 "C overnight. The reaction mixture was cooled to room temperature, filtered, and purified by reversed-phase HPLC using a gradient of acetonitrile in water (1-9995) and HCl as a modifier to give 2-cyclopropyl-6-(3-fluoro-4-methoxyphenoxy)-

M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide (100) (3.69 mg, 995). Mass/charge according to E5I-M5: calculated 524.10, found 525.2 (M-a-1)-. Holding time: 1.50 minutes (skipping Z

From the Minute).

EXAMPLE 41 (00288) Analytical data for the compounds of this invention are presented in Table 2 below.

Mass spectra (for example, the data of M.-1 in Table 2), final purity and retention time were determined using reversed-phase HPLC using a Kipeikh C18 column (50x2.1 mm, particles 1.7 μm) from РНепотепех (рп: 008- 4475-AM) and double passage of a 1-9995 gradient of mobile phase B for 3 minutes. Mobile phase А-Н2гО (0.0595 СезСО2Н). Mobile phase В-СНЗСМ (00595 СЕзбО2Н). The flow rate is 2 ml/min, the injection volume is 3 μl, and the column temperature is 50 °C (оО2891И

Table 2

Analytical data

Time (2) of the connection of the same MO in-yame (or Mhz) in minutes of radiation (OM50O-av) b 10.84 (s, 1H), 8.34-8.24 (m, 1H), 7.88 (d, 9-7.9 Hz, 1H), 1 1.96 455.3 | 7.82-7.72 (m, 1H), 7.64 (dd, 9U-7.9, 0.8 Hz, 1H), 7.60-7.47 (m, 2H), 7.40 ( s, 2H), 7.32-7.25 (m, 2H), 7.25-7.18 (m, 2H), 7.15 (s, 1H) m.h. 2 | 195 |473521 77777111

KU (OM50О-ав) b 10.81 (s, 1H), 8.30 (s, 1H), 8.01 (d, 9-2.3 Hz, 1H), 7.86-

From 1.86 455.5 | 7.78 (m, 2H), 7.59-7.53 (m, 2H), 7.39 (s, 2H), 7.35-7.24 (m, 4H), 7.00 (d, 9-8.7 Gu, 1H) m.h. 41 157 (44659771 pyt p EE PET A OO 6 11191 14735811 rzv duvyv (OM5O-av) b 10.65 (s, 1H), 8.30-8.24 (m, 1H), 7.81-7.72 (m, 1H), 7.68 7 1.8 435.15 (s, 1H), 7.58-7.48 (m, 2H), 7.38 (s, 2H), 7.29-7, 18 (m, 2H), 7.18-7.09 (m, 2H), 6.98 (s, 1H), 2.36 (s, ЗН) m.ch. ng: and o VES PO 9 | 158 42631771 158 14423111 (0M50-dv) b 10.84 (s, 1H), 8.33 (s, 1H), 8.20 (d, 9-2.0 Hz, 1H), 7.92 14 157 4461 ( d, U-8.7 Hz, 1H), 7.81 (d, 9U-6.9 Hz, 1H), 7.69 (dd, U-8.3, 2.8 Hz, 1H), " 7 17.60-7.54 (m, 2H), 7.48 (dd, 9-91, 5.2 Hz, 1H), 7.44-7.34 (m, ЗН), 6.88 (d, U-8.7 Hz, 1H) m.h. 12 | 66 (46981771 (0M50-dv) b 10.98 (s, 1H), 8.33 (s, 1H), 7.79-7.72 ( m, 1H), 7.61-7.48 13 1 61 485.3 (m, 4H), 7.40 (s, 2H), 7.20 (dd, 9U-8.9, 5.9 Hz, 1H) , 7.14 (dd, 9U-10.7, " "12.9 Hz, 1H), 6.93 (d, 9U-8.3 Hz, 1H), 6.84 (td, 9-84, 2 ,68 Hz, 1H), 3.77 (s, ZN) m.ch. 14 118 (48581... | 174 (y! 16 | 174 (y! 17 | 176 (455.71 18 | 183 (46959177 19 81 ( 43591777 | 179 (43591... (0M50-dv) b 10.73 (s, 1H), 8.30 (s, 1H), 7.75 (m, 1H), 7.54 (m, ЗН), 7.39 (s, 2H), 7.32 (m, 1H), 7.16 (dd, U-9.4, 2.9 Hz, 1H), 7.04 (td, " " T9u-8, 6, 3.2 Hz, 1H), 6.97 (dd, 9U-8.8, 5.1 Hz, 1H), 6.84 (dd, U-9,1,44

Hz, 1H), 2.18 (s, ЗН) m.h. 22 | 176 |46721 77777771 23 | 185 (48777771 24 | 182 (47277111 nvoi (OM50O-av) b 10.83 (s, 1H), 8.33 (s, 1H), 8.01 (d, 9-21 Hz, 1H), 7.81 1.81 469.2 | (m, 2H), 7.56 (m, 2H), 7.40 (s, 2H), 7.23 (ddd, U-13.9, 9.1, 4.0 Hz, 2H), 7.14 (td, U-8.6, 3.1 Hz, 1H), 6.82 (d, 9U-8.7 Gu, 1H), 2.15 (s, ЗН) m .h

here |nuoi (OM50O-av) b 10.84 (s, 1H), 8.32 (d, 9U-1.6 Hz, 1H), 8.04 (d, 9-2.1 Hz, 26 1, 78 489.2 | 1H), 7.82 (m, 2H), 7.69 (dd, U-8.4, 3.0 Hz, 1H), 7.56 (m, 2H), 7.47 ( dd, 9-91, 5.3 Hz, 1H), 7.37 (m, ЗН), 6.92 (d, U-8.7 Hz, 1H) m.ch. (OM5O-yv) b 10.74 (s, 1H), 8.33 (s, 1H), 7.97 (d, 9-2.2 Hz, 1H), 7.84 (m, 1H), 7 ,77 (dd, U-8,9,2,2 HC, 1H), 7.56 (m, 2H), 7.40 (s, 2H), 7.35 " | (dd, 9-8, 8, 5.9 Hz, 1H), 7.17 (dd, 9U-10.7, 2.9 Hz, 1H), 6.88 (td, 9-84, 2.9 Hz, 1H), 6, 79 (d, U-8.8 Hz, 1H), 3.75 (s, ZN) m.h. 28 | 73 (4852... 29 | 174 (av 80 | 19 |4852| : ССС

MET PI EH I PTO VO POLO

(ОМ50О-ав) 5 10.82 (s, 1H), 8.32 (s, 1H), 8.01 (s, 1H), 7.81 (s, 2H), ' "z |7.56 ( s, 2H), 7.26 (m, VN), 6.82 (d, U-8.3 Hz, 1H), 2.15 (s, ЗN) m.ch. zo loozhz (OM50O-av) b 11.02 (s, 1H), 8.32-8.25 (m, 1H), 7.73 (dt, 9-72, 2.0 Hz,

C3 1.77 489.3 | 1H), 7.69-7.60 (m, ЗН), 7.60-7.50 (m, 2H), 7.41 (c, 2H), 7.37-7.31 (m, 2) , 7.13-7.07 (m, 1H) m.h. (OM5O-dv) b 10.74 (s, 1H), 8.33 (s, 1H), 7.98 (d, 9-21 Hz, 1H), 7.84 (m, 1H), 7.77 (dd, 9U-8.9, 2.3 Hz, 1H), 7.56 (m, 2H), 7.40 (s, 2H), 7.31 ' "| (dd, 9-11.5, 4.6 Hz, 2H), 7.23 (m, 1H), 7.05 (td, 9U-7.7, 1.5 Hz, 1H), 6.78 (d, U-8.8 Hz, 1H), 3.74 (s, ЗН) m.p. (OM5O-dv) b 10.75 (s, 1H), 8.32 (s, 1H), 7.98 (d, 9-22 Hz, 1H), 7.83 (dt, 4-6.2, 2.4 Hz, 1H), 7.77 (dd, 9-8.9, 2.3 Hz, 1H), 7.56 (m, 2H ), ' "17.40 (s, 2H), 7.31 (dd, 9-54, 2.9 Hz, 2H), 7.11 (dd, U-8.5, 2.4 Hz, 1H) , 6.84 (d, 9U-8.8 Hz, 1H), 3.77 (s, ZN) m.h. 86 | 755 87 881 zo) in |yuvoi (OM50O-av) b 10.83 (s, 1H), 8.41-8.36 (m, 1H), 7.76 (dt, 9-71, 2.0 Hz , 38 1.72 435.5 | 1Н), 7.63-7.51 (m, ЗН), 7.39 (с, 2Н), 7.34-7.25 (m, ЗН), 7.12 -7.07 (m, 1H), 6.61 (t, U-8.0 Hz, 1H), 2.35 (s, ЗН) m.ch. (OM5O-dv) b 10.83 (s, 1H), 8.31-8.23 (m, 1H), 8.05 (d, 9U-2.3 Hz, 1H), 7.87 (dd, U-8.8, 2.2 Hz, 1H), 7.82-7.75 (m, 1H), 7.59-7.50 (m, 2H), ' "7 |7.50-7, 42 (m, 2H), 7.39 (s, 2H), 7.35-7.26 (m, 2H), 7.13 (d, 9U-8.8 Hz, 1H) m.h. (OM5O -dv) b 10.77 (s, 1H), 8.32 (s, 1H), 7.87 (s, 1H), 7.85-7.78 (m, 1H), 7.72-7, 64 (m, 2H), 7.60-7.53 (m, 2H), 7.39 (width, ЗН), 7.35 (d, 9-81 Hz, 1H), 7.10 (t , U-55.8 Hz, 1H), 6.89 (d, U-8.5 Hz, 1H) m.ch. .26 (m, 1H), 8.03 (d, 9-2.3 Hz, 1H), ' "7 |7.88-7.76 (m, 2H), 7.61-7.49 (m , 2H), 7.43-7.00 (m, 8H) m.h. 42 | 20 By (OM5O-dv) b 10.82 (s, 1H), 8.35-8.25 (m, 1H), 7.87 (d, 9U-7.9 Hz, 1H), 7.82- 7.73 (m, 1H), 7.62 (dd, 9-82, 1.6 Hz, 1H), 7.59-7.50 (m, 2H), 7.40 (s, 2H), 7 ,31-7.10 (m, ZN), 7.06-6.94 (m, 1H), 3.83 (s, ZN) m.h. 44 | 194 |4672| SSS | 201 fa 46 | 21 49547777 47 | 98 |a5t2| 77 48 | 20 |50e| 77777777 49 | 20 (48153 77777777 | 197 49574 in vya! (OM50O-av) b 10.86 (s, 1H), 8.26 (s, 1H), 7.91 (d, 9-7.9 Hz, 1H), 7.78- 51 2.08 521.4 | 7.68 (m, 2H), 7.60-7.49 (m, 2H), 7.45-7.38 (m, 4H), 7.36 (c, 1H), 7.26-7.19 (m, 2H) m.h.

Ba 91 (avBa av |nvo, (OM50O-av) b 10.82 (s, 1H), 8.36-8.28 (m, 1H), 7.85 (d, 9-7.8 Hz, 1H ), 53 2.05 495.5 | 7.83-7.76 (m, 1H), 7.61-7.49 (m, ЗН), 7.39 (s, 2H), 7.17-7 .08 (m, 2H), 7.07-6.93 (m, ЗН), 4.65-4.50 (m, 1H), 1.25 (d, U-6.0 Hz, 6H) m .h

(0M50-adv) b 10.68 (s, 1H), 8.37-8.30 (m, 1H), 7.84-7.79 (m, 1H), 7.77

BA 1.99 5012 (d, U-8.4 Hz, 1H), 7.60-7.50 (m, 2H), 7.40 (s, 2H), 7.37-7.28 (m, 1H) , ' 17.23-7.11 (m, 2H), 6.93-6.82 (m, 1H), 6.58-6.50 (m, 1H), 3.75 (s, ЗН)

M.ch. (0M50-dv) b 10.75 (s, 1H), 8.32-8.28 (m, 1H), 7.84-7.74 (m, 2H), 1.96 471.3 | 7.59-7.49 (m, 2H), 7.39 (s, 2H), 7.33-7.25 (m, ЗН), 7.25-7.18 (m, 2H), 6, 87-6.79 (m, 1H) m.h. (0M50-dv) b 10.77 (s, 1H), 8.36-8.28 (m, 1H), 7.82 (d, U-8.5 Hz, 1H), 56 2.0 505, 2 | 7.80-7.74 (m, 1H), 7.64 (dd, 9U-8.4, 2.9 Hz, 1H), 7.59-7.48 (m, 2H), 7.40 ( s, 2H), 7.38-7.26 (m, ЗН), 6.79 (d, U-2.2 Hz, 1H) m.h. 57 | 19 | 46717111 (0M50-dv) b 11.03 (s, 1H), 8.29 (t, 9-1.8 Hz, 1H), 7.72 (dt, U-7.3, 2.0 58 1, 34,485 Hz, 1H), 7.67-7.50 (m, 4H), 7.43 (d, U-2.5 Hz, 1H), 7.41 (s, 2H), 7.32 ( dd, 9U-8.6,2.7 Hz, 1H), 7.12-7.04 (m, 2H), 2.15 (s, ЗН) m.ch. (0M50-dv) b 11.05 (s, 1H), 8.29 (t, 9-1.8 Hz, 1H), 7.72 (dt, U-7.3, 2.0

Ba 1.26 469 Hz, 1H), 7.68-7.50 (m, 4H), 7.41 (s, 2H), 7.30 (td, U-8.2, 6.5 Hz, 1H), " 7.12 (d, 9-72 Gu, 1H), 7.10-7.04 (m, 1H), 6.91 (d, 9U-8.2 Hz, 1H), 2.08 (s, Zh) M. 60 1196 | 5 | 77777771 61 11720 (48561711 62 | 193 (577777777 63 | 189 Sh | 48791 77777771 64 | 187 (5955177777777777777777777777777777777777777777777777 (BY! 77777771 68 | 187 (52 77777771 p: so p SYA POST TKA OO (0M50-dv) b 10.83 (s, 1H), 8.35 (s, 1H), 7.87 (d, 9- 8.0 Hz, 1H), 7.84- 70 178 535.3 7.77 (m, 1H), 7.62-7.49 (m, ЗН), 7.40 (s, 2H), 7.32 ( dd, U-8.8, 5.9 Hz, ' "|1H), 7.16 (dd, U-10.6, 2.8 Hz, 1H), 6.88 (ddd, 9U-8.4 . s, 1H), 8.32-8.27 (m, 1H), 7.91 (d, U-7.9 Hz, 1H), 73 1.83 471 3 7.81-7.73 (m, 1H) , 7.73-7.65 (m, 1H), 7.61 (dd, 9U-8.0, 1.6 Hz, 1H), " "7 17.58-7.50 (m, 2H), 7.48-7.36 (m, ZN), 7.32-7.21 (m, 2H), 7.10 (d, 9-1.6

Hz, 1N) m.h. pi s Ex LY PE AL LO OO (СОзОб) b 8.31 (t, 9-2.0 Hz, 1H), 7.79 (ddd, 9U-8.1, 2.2,1.1 Hz, 1H ), 75 155 5О1 Z 7.68 (dt, 9-81, 1.3 Hz, 1H), 7.57-7.50 (m, 2H), 7.48 (d, U-7.8 Hz, 1H), " "17.16 (d, 9-9.0 Hz, 1H), 7.09 (d, 9-2.9 Hz, 1H), 6.93 (dd, 9-91, 2.4 Hz, 2H), 3.81 (s, ZN) m.h. (0M50-dv) b 10.67 (s, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.86-7.79 (m, 76 1.76 498.5 | 1H), 7.58-7.51 (m, 2H), 7.40 (s, 2H), 7.21 (d, 9-8.8 Hz, 1H), 6.78-6.71 ( m, 2H), 6.59 (dd, 9U-8.9, 2.8 Hz, 1H), 3.79 (s, ЗН), 3.74 (s, ЗН) m.h. (0M50-dv) 6 10.70 (s, 1H), 8.33-8.26 (m, 1H), 7.93 (s, 1H), 7.80 (dt, 77 174 485 3 9-64 , 2.3 Hz, 1H), 7.60-7.49 (m, 2H), 7.40 (s, 2H), 7.29 (dd, U-8.8, " "15.8 Hz, 1H), 7.14 (dd, 9U-10.7, 2.9 Gu, 1H), 6.89-6.79 (m, 2H), 3.76 (s,

ZN) m.ch. (0M50-dv) b 10.77 (s, 1H), 8.28-8.23 (m, 1H), 7.98 (s, 1H), 7.76 (dt, 78 1.70 455.5 |9-6.9, 21 Hz, 1H), 7.59-7.49 (m, 2H), 7.39 (s, 2H), 7.26 (t, 9-8.7 Gu, 2H) , 7.22-1.16 (m, ZN) m.h. (0M50-dv) b 10.74 (s, 1H), 8.29-8.23 (m, 1H), 7.96 (s, 1H), 7.77 (dt, 79 1.70 485.3 |9-7.0,2.2 Hz, 1H), 7.60-7.50 (m, 2H), 7.40 (s, 2H), 7.25-7.14 (m, ЗН), 6.97 (dt, y-9.4, 1.9 Hz, 1H), 3.83 (s, ZN) m.ch.

(0M50-dv) b 10.80 (s, 1H), 8.32-8.28 (m, 1H), 7.96 (s, 1H), 7.80 (dt, 1.82 5OZ 96.6 , 2.2 Hz, 1H), 7.59-7.51 (m, 2H), 7.40 (s, 2H), 7.29 (t, 9-92 Hz, " " |1H), 7, 06 (dd, 9-12.6, 2.9 Hz, 1H), 7.01 (s, 1H), 6.84 (ddd, U-9.1, 3.0, 1.3 Hz, 1H) , 3.78 (c, ZN) m.h. (0M50-dv) b 10.80 (s, 1H), 8.32-8.28 (m, 1H), 7.96 (s, 1H), 7.80 (dt, vi 172 485 3 96.6 , 2.2 Hz, 1H), 7.61-7.51 (m, 2H), 7.40 (s, 2H), 7.29 (t, 9-92 Hz, " "|1H), 7, 06 (dd, 9U-12.6, 2.9 Hz, 1H), 7.01 (s, 1H), 6.84 (ddd, uU-9.1, 3.0, 1.3 Hz, 1H) , 3.78 (c, ZN) m.h. (0M50-dv) b 10.77 (s, 1H), 8.33-8.28 (m, 1H), 7.98 (s, 1H), 7.79 (dt, vo 18 5O1 Z 96.6 , 2.2 Hz, 1H), 7.59-7.51 (m, 2H), 7.40 (s, 2H), 7.32 (d, 9-9.0 Hz, ' "1 H), 7.20 (d, 9U-3.0 Hz, 1H), 7.02 (dd, U-9.0, 3.0 Hz, 1H), 6.89 (s, 1H), 3.79 (s , ЗН) m.ch. 83 1.78 469.3 |9-7.0, 21 Hu, 1H), 7.62-7.50 (m, 2H), 7.40 (s, 2H), 7.21 (dd, 9- 94, 2.9 Hz, 1H), 7.15-7.04 (m, 2H), 6.95 (s, 1H), 2.17 (s, ЗН) m.h. (0M50-dv) b 10.55 (s, 1H), 8.32 (s, 1H), 7.82 (d, 9-3.5 Hz, 1H), 7.67 and 1.65 463 З (d, 9-8.2 Hz , 1H), 7.62-7.51 (m, 2H), 7.39 (s, 2H), 7.30-7.19 (m, 2H), 16.76 (d, U-2 ,7 Hz, 1H), 6.60 (dd, U-8.8, 2.7 Hz, 1H), 6.56 (d, 9-1.8 Gu, 1H), 3.79 (s, ZN ), 3.75 (c, ZN) m.h. 85 | 11 (46711111 (0M50-dv) b 10.60 (s, 1H), 8.30 (s, 1H), 7.80 (width, s, 1H), 7.68 (d, 1.67 467.1 19-8.2 Gu, 1H), 7.63-7.50 (m, 2H), 7.39 (s, 2H), 7.32-7.20 (m, ZN), 7.13-7 ... (s, 1H), 8.25 (t, 9-1.8 Hz, 1H), 7.99 (s, 1H), 7.72 88 1.77 523.2 | (dt, 97.4, 1 .9 Gu, 1H), 7.63-7.52 (m, 2H), 7.48 (s, 1H), 7.43 (s, 2H), 7.37-1.22 (m, 4H) m.ch. 89 | 187 15532771 90 | 183 (55277771 91 1187 55800371 92 | 185 55523771 93 | 193 | 5MYA 77777777 (0M50-dv) b 11.06 (s, 1H), 8.30 (s, 1H) 7.77-7.71 (m, 1H), 7.59-7.52 94 1.57 455.3 | (m, ЗН), 7.41 (s, 2H), 7.29 (dd, 9U -8.7 Hz, 2H), 7.25-7.19 (m, 2H), 6.90 (d, U-1.8 Hz, 1H) m.h. (0M50-dv) b 11.02 (c, 1H), 8.34 (c, 1H), 7.81-7.74 (m, 1H), 7.61-7.53 95 1.58 485 5 (m, 2H), 7.48 (d, 9U-1.8 Hz, 1H), 7.41 (s, 2H), 7.21 (dd, 9U-8.8, 5.8 Hz, " "IN), 7.15 (dd, 9U-10.6, 2.9 Hz, 1H), 6.89-6.81 (m, 1H), 6.60 (d, 9U-1.8

Hz, 1H), 3.78 (s, ЗН) m.h. 96 | 164 (46991777 97 | 13 (53777771 98 | 168 |5MZ 77777771 pis: Sya o EH: o PE: SYA PO loya | 15 |552|p77777777777111111111111111111111111111111

EXAMPLE 42

ANALYZES FOR DETECTION AND MEASUREMENT OF THE PROPERTIES OF INHIBITING Mach COMPOUNDS

Method of optical analysis of membrane potential E-MIRE. with electrical stimulation

I00290| Sodium channels are potential-dependent proteins that can be activated by inducing changes in membrane voltage by applying electric fields. The device for electrical stimulation and methods of application are described in (Op SNappe! Azzau Meshtoa5

PCT/О5О1/21652, incorporated in this document by reference, and marked as E-MIRK. The device includes a holder for a microtitration tablet, an optical system for excitation of the coumarin dye with simultaneous registration of coumarin and oxonol radiation, a wave signal generator, a controlled current or voltage amplifier, and a device for inserting electrodes into the well. Under the control of the built-in computer, this device performs electrical stimulation of the cells in the wells of the microtiter plate programmed by the user according to the protocol.

I00O291| 24 hours before E-MIRK analysis, NEK cells expressing human Mau1.8 were seeded in 384-well plates coated with polylysine at 15,000-20,000 cells per well. NEK cells were grown in media (the exact composition is specific for each cell type and Mau subtype) supplemented with 10 95 EVZ (embryonic calf serum, certified; sirsovki.

YAZh16140-071) and 195 Rep-5iger (penicillin-streptomycin; (irsSOVKI zh15140-122). Cells were grown in flasks with a lid with a hole, at 90 95 humidity and 5 95 CO".

Reagents and solutions (002921) 100 mg/ml Pluronic E-127 (Zidta ZHR2443) in dry OM5O.

I00293| Compound plates: 384-well round-bottom plates, such as Sogpipe's 384-well polypropylene round-bottom plate 23656.

I00294| Cell plates: 384-well plates processed for cell culture, such as Ogeipeg 2781091-18. (002951) 10 mm rizvdAsv (3) (Aeygoga ZHO0-100-010) in dry OM5O. (00296) 10 mm SS2-OMRE (Aga 2500-100-008) in dry OM5O. (00297) 200 mm AVZSI1 in H2O. (00298) Wash buffer 1: glucose 10 mM (1.8 g/L), magnesium chloride (anhydrous) 1 mM (0.095 g/L), calcium chloride 2 mM (0.222 g/L), HERE5 10 mM (2 .38 g/l), potassium chloride 4.5 mm (0.335 g/l), sodium chloride 160 mm (9.35 g/l).

I00299| Hexyl dye solution: buffer for washing 1-0.5 95 DV-cyclodextrin (obtained before use, bidta Zh2ZhS4767) 8 µm CC2-OMREh2.5 µm ribvaAsv(3). To obtain the solution, a volume of 10 95 of the initial solution of pluronic E127, equal to the volume of SS2-OMREzhRIiZVASv(3), was added. Preparation procedure: first, pluronic and

СбС2-ОМРЕ, then rizvАсСб(3) was added with shaking, then buffer for washing 1--рД-cyclodextrin was added.

Analysis protocol 00300) 1) Preliminarily, spots of compounds (in pure OM5O) were applied to tablets for compounds.

Control vehicle (pure OM5O), positive control (20 mM tetracaine stock solution in

OM5O, final assay concentration 125 μM) and test compounds were added to each well at 160x the desired final concentration in pure OM5O. Final volume in the compound tablet

Zo was 80 μl (80-fold intermediate dilution from 1 μl spot in MBO; 160-fold final dilution after transfer to the cell plate). The final concentration of OM5O for all wells in the analysis was 0.625 95. (0030112) A solution of hexyl dye was obtained. (00302) 3) Tablets with cells were obtained. On the day of the analysis, the medium was removed and the cells were washed three times with 100 μl of washing solution 1, keeping a residual volume of 25 μl in each well. 00303) 4) Distributed 25 μl per well of hexyl dye solution in cell plates. Incubate for 20-35 minutes at room temperature or ambient conditions. 00304 5) Distributed 80 μl per well of buffer for washing 1 in tablets for compounds.

Acid yellow-17 (1 mM) was added and potassium chloride varied from 4.5 to 20 mM depending on the subtype of Mam and the sensitivity of the assay.

I00305| 6) Wash cell plates three times with 100 μl per well of wash buffer 1, leaving 25 μl of residual volume. Then, 25 μl per well were transferred from compound plates to cell plates. Incubate for 20-35 minutes at room temperature/ambient conditions. 00306) 7) Tablets were read on E-MIRK. A controlled current amplifier was used to deliver stimulating wave pulses for 10 seconds and at a scan rate of 200 Hz. Registration before stimulation was carried out for 0.5 seconds to obtain baseline intensity values without stimulation. The stimulating waveform was followed by 0.5 seconds of recording after stimulation to study the relaxation of the cells to a resting state.

Data analysis

IІ00307| The data were analyzed and recorded in the form of normalized ratios of radiation intensity measured in the 460 nm and 580 nm channels. The response as a function of time was recorded in the form of ratios obtained using the following formula:

В(d- (intensify 4bO nm-- output value of 460 nm) (intensify 58O nm-- output value of 580 nm)

(00308) The data were further simplified by calculating initial (Ki) and final (KE) ratios. They were the average values of the ratios during the partial or full period before the stimulation, and at the measurement points during the stimulation period. Then the response to the K-KR/KI stimulus was calculated; and recorded as a function of time.

I00309| Response control values were obtained by performing assays in the presence of a compound with desired properties (positive control), such as tetracaine, and in the absence of pharmacological agents (negative control). Responses to negative (M) and positive (P) controls were calculated as above. The activity of antagonist A compound is determined as: d-H-E,100

M-P, where K is the response ratio for the tested compound.

ELECTROPHYSIOLOGICAL ANALYZES FOR DETERMINING Mach ACTIVITY AND INHIBITION

TESTED COMPOUNDS

I00310| The electrophysiological method of potential fixation was used to assess the effectiveness and selectivity of sodium channel blockers in dorsal root ganglion neurons. Rat neurons were isolated from the dorsal root ganglia and maintained in culture for 2-10 days in the presence of MOB (50 ng/ml) (culture medium consisting of MeihorazatA supplemented with B27, glutamine and antibiotics). Neurons of small diameter (nociceptors with a diameter of 8-12 μm) were identified visually and probed with thin tips of glass electrodes connected to an amplifier (AkhOp Ipsigitepov). The "voltage-clamp" mode was used to evaluate the IC of the compound, holding the cells at -60 mV.

In addition, the "current-clamp" mode was used to test the effectiveness of the compounds in blocking the occurrence of action potentials in response to current stimulation. The results of these experiments contributed to the definition of the performance profile of the compounds.

I00311| The compounds illustrated in Table 1 herein exhibit activity against Mau1.8 sodium channels as measured using the assays described herein and as presented in Table C below.

From (003121

Table C

ISzo of activity for Mam1.8 7776 |... 003 2 ЩЩЬ/ 28111116 71 77778. 0028 ЩЩ

Table C

ISzo of activity for Mam1.8 777760 YuyuYUBKB;khtsiu0/oDluchs 77766 | Byuzhshch 0007 77768 Yuyu. BUYYUY7Bul7ob009 21 777769 | Byuzhf 0026 9 Sh

Table C

ISzo of activity for Mam1.8 80... 0004272 786 |... 70015 щЩщ Kr 2898 777711110001 272 77790. yur ryu.0007 2 щYug 77796... yur o0001 721 77798... yur bo008 1 77799... .- .YuyuYuYIro0005

EXAMPLE 43 (00313) Analysis for Iopumogk5. This assay was performed to determine the activity of compounds of the present invention against non-Mau1.8 channels. Sodium currents were recorded using an automatic system with potential fixation, IopumMogk5 (MoiIesshag Oemise5

Sogrogayop, Ips.). Cells expressing Mau subtypes were collected from tissue culture and suspended at 0.5–4 million cells per ml of wash buffer 1. The IopUmog5 device measured changes in sodium currents in response to an applied holding potential in a manner similar to the conventional holding potential assay , except for the 384-hole format. Using Iopumogk5, the dose-response relationship was determined in voltage-clamp mode by depolarizing the cells from an experiment-specific starting potential to a test potential of approximately 0 mV before and after addition of the test compound. The effect of the compounds on the currents was measured at the test potential.

EXAMPLE 44 00314) Protocol for the analysis of human liver microsomes. Data on the stability of liver microsomes were obtained as follows. The substrates were incubated at 37 "C and shaken for 30 minutes in a phosphate-buffered solution with human liver microsomes and the MAYURN cofactor.

A zero-time control was obtained in the same way, but with the exception of MAORN.

The final concentrations during incubation were 1 μM substrate (0.2 95 ЮОМ5О), 0.5 mg/ml liver microsomes, 2 mM MAORN and 0.1 M phosphate. Reactions were stopped and proteins were precipitated by adding 2 volume equivalents of ice-cold acetonitrile containing an internal standard.

After the centrifugation stage, aliquots from the incubation mixtures after stopping the reaction were additionally diluted with 4 volume equivalents of 50 95 aqueous methanol solution, and then subjected to the analysis of I! C/M5/M5 for quantitative evaluation of the original substrate. Microsome stability values were calculated as the percentage of substrate remaining after 30 minutes relative to the time zero control. 00315) Table 4. Human liver microsome (HIM) data for selected compounds of the present invention are listed below. Values presented are the percent of compound remaining after 30 minutes using the protocol described above in Example 44.

Of the compounds with a reported 2100, 95 percent unchanged after 30 minutes of incubation represent compounds that were not metabolized under the assay conditions. Values greater than 100 95 were due to analytical quantification variability in the assay.

Abbreviation "MO" means no data.

Table 4 summarizes M solution

Mo compounds after 30 min. 77176706 7777687 B111708 778. B111702 710.1 86 Currents SHE 11111. 86 712118 Its 98 2 277720 ....Yuyuyuyyyyyyu'177 "I eat YuzhZh".

Table 4 oozhoyulyu M rev

Mo compounds after 30 min. now she is 111154 HER юЮюЮБмжКужЙ86 g 71171758... | .ЮЙМКЬ1 66 СС 7776092 2 щ никлиншишши ши 7777764 ЮЩ(.Ї БюЮжщКЖ96 г « 777366 | .-.юЮЙЙЙ89 6 ЖжЖКршщБ--" 7777768 2 щЮщЮЙЇ 80 г Фж -Б9 77775769 | юю 228077 Ї177711111170811 771786... 82 2881 Ї111111171871 790.92 2 7795 ХІ ..ХХХХХХХ96 g ХФ Кий 7775796... |

I00316| Many modifications and changes to the embodiments described herein can be made without departing from its scope, as will be apparent to those skilled in the art.

The specific implementation options described in this document are offered by way of example only.

Claims (38)

FORMULA OF THE INVENTION 1. The compound of the formula I voFny - y g MM M "junu kocho o - and "U g" is also Y or its pharmaceutically acceptable salt, where, independently for each occurrence: V' represents H, SI, CH3, CEz or cyclopropyl; B2 is Н, Е, СИ, СМ, СН3, СЕ3 or СНЕ"; ВZ is Н, Е, СИ, СМ, СЕз, ОСЕз or СЕ2СЕ z; B" represents H; B" represents H, E, SI, CH3, OSH3, OSNoCH3, OSNaCHoCH" or OSNE"; B" represents H, HE, CI, CH3, OSH3, OSNaCH3, OSNa.CHoCnH" or OSNE "; A represents H, E, or Si; A represents H, E, or Si; and B' represents H, E, Si, OSH3, OSE3, OSH:CH", OSH(CH33)" or OSNE", according to conditions that KE", V? and EZ at the same time do not represent hydrogen; and that E-, B", Ne, Ve and B" are not hydrogen at the same time. 2. The compound or salt according to claim 1, where E" is H, CEz or SI. 3. Compound or salt according to claim 1 or 2, where KE! is H or SEz. 4. Compound or salt according to any of claims 1-3, where B? is H, SEz or SI. 5. Compound or salt according to claim 4, where K? is H or CE. 6. A compound or salt according to any of claims 1-5, where KU is H, CE", SI or OSE". 7. The compound or salt according to claim 6, where KZ is H, SEz or SI. 8. The compound or salt according to any of claims 1-7, where EC? is N. 9. A compound or salt according to any of claims 1-8, where K5 or KU is H or EK. 10. The compound or salt according to any of claims 1-9, where K" is E, SI, OSN3 or ОСЕ:. Ko) 11. The compound or salt according to claim 10, where K" represents E or OSN". 12. The compound or salt according to claim 1, where the compound has the formula 1-0: NA and pH. 0 MH; yo Kk i-o where, independently for each occurrence: B2 represents E, SI, CM, СН3, SE3 or СНЕ"; IN? is Е, СИ, СНз, ОСНзи, ОСНаСНзи, ОСН".СНесСН" or ОСНЕ"; and B" represents PE, SI, OSN3, OSE3, OSNoCH", OSN(СН33)2 or OSNE». 13. Compound or salt according to claim 12, where is KE? is Si or SEz. 14. Compound or salt according to claim 12 or 13, where EE? is E, SI, CH3 or OSN". 15. The compound or salt according to any of claims 12-14, where ВЕ" represents Е, СИ, OSН3 or ОСЕ»3. 16. The compound or salt according to claim 1, where the compound has the formula I-E: and in ! С noОоофчн, В ( yo in TE where, independently for each occurrence: ВZ represents Р, СИ, СМ, СЕз, ОСЕз or СР»СЕ:; В: represents РЕ, СИ, СНз, OSНз, OSН.СНз, OSNaСНоСН " or OSNE"; and B" represents Е, СИ, OSН3, ОСЕ3, OSН»СН", OSН(СНЗ3)» or OSNE». 17. The compound or salt according to claim 16, where KZ is SI, SEz or ОСЕ:. 18. The compound or salt according to claim 16 or 17, where EC" represents EC, SI, CHz or OSN". 19. The compound or salt according to any of claims 16-18, where K" represents EK, SI, OSNz or OSE". 20. The compound or salt according to claim 1, where the compound or its pharmaceutically acceptable salt is selected from the group that includes: -4-(trifluoromethyl)benzamide; Shchy and "Mn. it NM. about E E ABOUT. 2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide; Zm C "MH; not -0 "0 E SEZ 2-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide; dod I NM o IX, E -4 s CI M 2-(2-chloro-4-fluorophenoxy)-4-cyano-M-(3-sulfamoylphenyl)benzamide; b NM. B-chloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide; Zm "Mn; NM o E and E SEZ 2-(2,4-difluorophenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide; b and ky "MH. share NO. in. I am! E SN. c 4-chloro-2-(4-fluorophenoxy)-5-methyl-N-(3-sulfamoylphenyl)benzamide; 4-chloro-2-(2-chloro-4-fluorophenoxy)-M-(3-sulfamoylphenyl)benzamide; 4-cyano-2-(4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)benzamide; wow NM. what With o. h vl osn (in M 4-cyano-2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide; brony NM. sa E ; Cha Z 2-(2-chloro-4-fluorophenoxy)-5-cyano-N-(3-sulfamoylphenyl)benzamide; o, - "many Shish pa in ml eE СМу 2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide; at. schi "Mne ni o geo" E Osn. 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide; and B "MN, NM. 2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide; b NM. 4-chloro-2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide; (at NM. lo se nt k EOM OH» with B-chloro-2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide; B in, MH» НІ (9: To "o B-chloro-2-(2-chloro-4-fluorophenoxy)-M-(3-sulfamoylphenyl)benzamide; 4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide; р С МН» НМ о въже; ше Е CH, о 4-chloro-2-(4-fluoro-2 -methylphenoxy)-M-(3-sulfamoylphenyl)benzamide; that and ul mn. rya NM sho se i shi shchi E Sn. c B-chloro-2-(4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)benzamide; oh shh NM. what is: ac: B-fluoro-2-(4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)benzamide; 2-(4-methoxyphenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide; C not 19) BO SEZ 2-(4- ethoxyphenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide; beat NM. 2-(4-chlorophenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide; bod C nmche CH, and E CE 2-(4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide; NM. lo Si tu v. | "CE 2-(2-chloro-4-fluorophenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide; no I) asne sg Shchi E What 2-(4-fluoro-2-methoxyphenoxy)- M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide; I am from Kk NM. 2 washes of 2-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide; ozh 7 Me "MN, where M o Basic c SEZ 2-(3-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide; at. and NM what? SN. 2-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide; still ts - NYA no other; 2-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide; бы "щН,. nm o Сн о M-(3-sulfamoylphenyl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide; ой НМ о си СС 7 ры 2-(2-chloro-4-fluorophenoxy) -M-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide; NM. -O osn, 'C 2-(2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide; With the honor of Fr Basic Me sh--o ; with ; ; | t c Sta 2-(4-chloro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide; Oh KS NM. 2-0 Osn; 2-(2,4-dimethoxyphenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide; b Mn, NM. lo so 2-(4-isopropoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide; Z and Ko) c and 4 2-(2-chloro-4-fluorophenoxy)-6b-methyl-N-(3-sulfamoylphenyl)benzamide; M-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide; More. "Mneshchi n E si M 2 s ! EE E - KE 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-M-(3-sulfamoylphenyl)benzamide; Z nie NM -0 / SU". 2-(4-(difluoromethoxy)phenoxy)-M-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide; B with "Mn, -E NM Basic 2-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide; b NM. 2-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide; From "MN, NC. at Basic 2-(2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-"(trifluoromethyl)benzamide; 2-(4-ethoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide; oh, - S MN" NM. o g Oto CEz 2-(2-propoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide; Sha NM. -o SV and without M-(3-sulfamoylphenyl)-2-(o-tolyloxy)-4-(trifluoromethyl)benzamide; o, and More "MH. more m What) 2-(2-chloro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide; b? MH NM. - Oh sleep and swarm Sk. 2-(4-methoxy-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide; b MN NM ge) Basic C note 4 SEz 2-(2,4-dimethoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide; b wed what NM. but ECO - and SEZ M-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide; rai NM no Osn, E he ho) sia S - - SE. 2-(3-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide; would Zh "Mn, ryh NM o o A SE. 2-(4-isopropoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide; Ouavsk, rya polk NI O Osn SS E sho i OSK, 2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide; 2-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide; 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide; oh me NM. 0 basis 2-(2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-6-"(trifluoromethyl)benzamide; B Dy And with NM. -at SN. ! 2-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-6-"(trifluoromethyl)benzamide; would! and NM. -o ON Z and ho S! SE. 2-(3-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide; "many NM. M-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)benzamide; this "Mn; NM. O-O: 2-(3-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide; B u nn, - НМ 0-0 s and nso B Ost, 2-(2-chloro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide; From one (o) si: OSE 2-(2-chlorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide; byy E AJ NM. 2 E o ste OSCE. 2-(2-(difluoromethoxy)phenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide; ody NM Fi Osn, I DS di i ge M OS; 2-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide; 2-(3-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide; For NM. -0 us - | o CEx 2-(3-chloro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide; bi shk (F. osv Se as h- СО dО СЕ, 2-(3-chloro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide; WE. o va I vl - ri as E 2-(4-fluorophenoxy)-4-(perfluoroethyl)-M-(3-sulfamoylphenyl)benzamide; b I "Mn; NM. Basis of VL E as E 2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-M-(3-sulfamoylphenyl)benzamide; With 8. Osn; DS se yah from the Russian Federation. K.S E 2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-M-(3-sulfamoylphenyl)benzamide; b ne NM no si neo Z : STE 2-(2-chloro-4-methoxyphenoxy)-4-(perfluoroethyl)-M-(3-sulfamoylphenyl)benzamide; He NM. -0 С Cg (fi CE 2-(2-chlorophenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide; biy "Mn; НМ о с ; и сх 2-(2-chlorophenoxy)-М- (3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide; o, schi "MH; NM o osn"; also SS neo -4 Si s 4,5-dichloro-2-(2,4-dimethoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide; b Z "Mne 4 NM. lo usn, etc. E S. c 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide; ZU in MN, and r NM. 9) SIS and | la EE SI with 4,5-dichloro-2-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)benzamide; With shchi I. and NM novel: SI with 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide; NM. sho Osn; uosh ot ; (I se! SI 4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide; in "Mn, NM. 4,5-dichloro-2-(2-fluoro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide; Bia "MN. NM. 4,5-dichloro-2-(2-chloro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide; -2-(4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)benzamide; oh, not 0 yet Basic what! oiren neo Si 4-chloro-2-(2,4-dimethoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; by "MN; NM. and also vy NK with 4-chloro-2-(4-chloro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide; I NM. -0 Si y ng y C 4-chloro-2-(2-chloro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide; Diluted in water: Ha Si 4-chloro-2-(4-isopropoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide; b So NM. I'm sending E also CE". 2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide; From "Mn" ONA o Osn" in Z ke | SEZ EL: Sk. 2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide; b "Me NM. sho 0 SEZ nso7 » | Z K Ka 2-(3-fluoro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide; and "MN; NM E in (8) SE. 2-(2-fluoro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide; because yah NM sho ost. c o SR E Cg 2-(5-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide; b To me NM. 6; St su CE E and SEZ 2-(4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide; 2,4-dichloro-6-(4-fluorophenoxy)-M-(3-sulfamoylphenyl)benzamide; NM. 2,4-dichloro-6-(4-fluoro-2-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide; brya -y nm (o) c y - kl E F - C 2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-M-(3-sulfamoylphenyl)benzamide; From in, ZKMn; NM. 2,4-dichloro-N-(3-sulfamoylphenyl)-6-(4-(trifluoromethoxy)phenoxy)benzamide; battle "Me NM. lo Osn; 2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide; Ok che "MH; NM o E ; SU o. si se. Y ion 2,4-dichloro-6-(2-fluoro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)benzamide and p NM. 2-cyclopropyl-6-(3-fluoro-4-methoxyphenoxy)-M-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide; or a pharmaceutically acceptable salt thereof. 21. A pharmaceutical composition containing a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-20 and one or more pharmaceutically acceptable carriers or binders. 22. A pharmaceutical composition containing a compound or a pharmaceutically acceptable salt according to any one of claims 1-20 and one or more pharmaceutically acceptable carriers or binders. 23. A method of inhibiting a potential-dependent sodium channel in a subject, which includes administering to the subject the compound or its pharmaceutically acceptable salt according to any of claims 1-20 or the pharmaceutical composition according to claim 21 or 22. 24. The method according to claim 23, where the potential-dependent sodium channel is Mau1.8. 25. A method of treating or reducing the severity of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, malignant tumor pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis in a subject , Charcot-Marie-Tooth syndrome, urinary incontinence or cardiac arrhythmia, which comprises administering an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-20 or a pharmaceutical composition according to claim 21. 26. The method of claim 25, which includes treating or alleviating the severity of intestinal pain in the subject, wherein the intestinal pain includes inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain. 27. The method of claim 25, which includes treating or alleviating the severity of neuropathic pain in a subject, wherein the neuropathic pain includes postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton's neuroma; injury with pinched nerve, spinal stenosis, carpal tunnel syndrome, sciatica, sciatica; injury with rupture of the nerve, injury with rupture of the brachial plexus; complex regional pain syndrome, neuralgia induced by drug therapy, neuralgia induced by chemotherapy of a malignant tumor, neuralgia induced by antiretroviral therapy; pain after spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic cephalgia. 28. The method of claim 27, wherein the neuropathic pain comprises idiopathic small fiber neuropathy. 29. The method of claim 27, wherein the neuropathic pain comprises postherpetic neuralgia. 30. The method of claim 25, which includes treating or alleviating the severity of musculoskeletal pain in the subject, wherein the musculoskeletal pain includes osteoarthritis pain, spinal pain, cold pain, burn pain, or tooth pain. 31. The method according to claim 30, wherein the musculoskeletal pain includes osteoarthritis pain. 32. The method of claim 25, which includes treating or alleviating inflammatory pain in the subject, wherein the inflammatory pain includes rheumatoid arthritis pain or vulvodynia. 33. The method of claim 25, which includes treating or alleviating the severity of idiopathic pain in a subject, wherein the idiopathic pain includes fibromyalgia pain. 34. The method according to claim 25, which includes treating or reducing the severity of acute pain in a subject. 35. The method of claim 34, wherein acute pain includes postoperative pain. 36. The method according to claim 25, which includes treating or reducing the severity of postoperative pain in the subject. 37. The method of claim 25, which includes treating or reducing the severity of visceral pain in a subject. 38. The method of any of claims 23-37, wherein said subject is treated with one or more additional therapeutic agents administered during, before, or after treatment with the compound, salt, or pharmaceutical composition.